Genetic Variant NM_153704.6:c.958A>T (chr8-93780962-A-T) – ACMG Classification: Likely_benign (-2 pts)

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.029471219).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM67	NM_153704.6 link	c.958A>T	p.Ser320Cys	missense_variant	Exon 9 of 28	ENST00000453321.8	NP_714915.3	Q5HYA8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM67	ENST00000453321.8 link	c.958A>T	p.Ser320Cys	missense_variant	Exon 9 of 28	1	NM_153704.6	ENSP00000389998.3		Q5HYA8

Frequencies

GnomAD3 genomes

AF:

0.000821

AC:

125

AN:

152252

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.00272

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000390

AC:

98

AN:

251056

Hom.:

0

AF XY:

0.000339

AC XY:

46

AN XY:

135758

show subpopulations

Gnomad AFR exome

AF:

0.00316

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.000282

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000244

AC:

356

AN:

1456834

Hom.:

1

Cov.:

30

AF XY:

0.000244

AC XY:

177

AN XY:

724950

show subpopulations

Gnomad4 AFR exome

AF:

0.00258

Gnomad4 AMR exome

AF:

0.000335

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000465

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.000202

Gnomad4 OTH exome

AF:

0.000283

GnomAD4 genome

AF:

0.000853

AC:

130

AN:

152370

Hom.:

0

Cov.:

32

AF XY:

0.000738

AC XY:

55

AN XY:

74514

show subpopulations

Gnomad4 AFR

AF:

0.00284

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000254

Hom.:

0

Bravo

AF:

0.000926

TwinsUK

AF:

0.00

AC:

0

ALSPAC

AF:

0.000519

AC:

2

ESP6500AA

AF:

0.00340

AC:

15

ESP6500EA

AF:

0.00

AC:

0

ExAC

AF:

0.000453

AC:

55

Asia WGS

AF:

0.00260

AC:

9

AN:

3472

EpiCase

AF:

0.000600

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:14Benign:1Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:5

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 29, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 31, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in an individual in published literature who was also found to have another TMEM67 variant (G218A) on the same allele (in cis), and had a different genetic etiology for the phenotype (Leitch et al., 2008); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 20981092, 20690115, 27336129, 20301537, 34426522, 18327255) -

COACH syndrome 1

Uncertain:2

Mar 29, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 26, 2019

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not specified

Uncertain:1

Dec 15, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TMEM67 c.958A>T (p.Ser320Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00039 in 251056 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TMEM67 causing Joubert Syndrome 6 (0.00039 vs 0.004), allowing no conclusion about variant significance. c.958A>T has been reported in the literature in individuals affected with Bardet-Biedl syndrome and Cohen syndrome, in which pathogenic variants from other genes were identified to be the genetic cause (example, Dixon-Salazar_2012, Leitch_2008). These report(s) do not provide unequivocal conclusions about association of the variant with Joubert Syndrome 6. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect as the Zebrafish modeling and the rescuing phenotype of developmental delay are not appropriate for evaluating this variant (Leitch_2008). The following publications have been ascertained in the context of this evaluation (PMID: 22700954, 18327255). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=7, Likely benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Meckel syndrome, type 3

Uncertain:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

RHYNS syndrome

Uncertain:1

Oct 02, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3. -

Nephronophthisis 11

Uncertain:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Meckel syndrome, type 3;C1853153:Joubert syndrome 6;C1865794:RHYNS syndrome;C2673874:Bardet-Biedl syndrome 14;C3150796:Nephronophthisis 11;C5435651:COACH syndrome 1

Uncertain:1

Aug 20, 2020

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Joubert syndrome 6

Uncertain:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

TMEM67-related disorder

Uncertain:1

Sep 04, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TMEM67 c.958A>T variant is predicted to result in the amino acid substitution p.Ser320Cys. This variant in TMEM67 (also known as MKS3) has been reported in cis with TMEM67 c.653G>C in a patient with Bardet-Biedl syndrome, who also carried a homozygous CEP290 nonsense variant (Leitch et al 2008. PubMed ID: 18327255).This variant is reported in 0.30% of alleles in individuals of African descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis

Benign:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bardet-Biedl syndrome 14, modifier of

Other:1

Apr 01, 2008

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nephronophthisis

Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.057

T

BayesDel_noAF

Pathogenic

0.14

CADD

Uncertain

26

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.80

D;D;.

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

D

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Pathogenic

0.44

D

MetaRNN

Benign

0.029

T;T;T

MetaSVM

Pathogenic

0.95

D

MutationAssessor

Uncertain

2.6

.;M;.

PrimateAI

Benign

0.41

T

PROVEAN

Uncertain

-3.2

D;D;D

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.67, 0.67

MVP

1.0

MPC

0.55

ClinPred

0.084

T

GERP RS

4.7

Varity_R

0.39

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

NM_153704.6:c.958A>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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