rs111619594

chr8-93780962-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_153704.6(TMEM67):c.958A>T(p.Ser320Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000302 in 1,609,204 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (1 hom.)
• Consequence: TMEM67 NM_153704.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:13 B:1 O:2
• Conservation: PhyloP100: 8.64

Genes affected

TMEM67 (HGNC:28396): (transmembrane protein 67) The protein encoded by this gene localizes to the primary cilium and to the plasma membrane. The gene functions in centriole migration to the apical membrane and formation of the primary cilium. Multiple transcript variants encoding different isoforms have been found for this gene. Defects in this gene are a cause of Meckel syndrome type 3 (MKS3) and Joubert syndrome type 6 (JBTS6). [provided by RefSeq, Nov 2008]

ACMG classification

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/exons	MANE	UniProt
TMEM67	NM_153704.6	c.958A>T	p.Ser320Cys	missense_variant	9/28	ENST00000453321.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM67	ENST00000453321.8	c.958A>T	p.Ser320Cys	missense_variant	9/28	1	NM_153704.6	P1

Frequencies

GnomAD3 genomes AF: 0.000821 AC: 125 AN: 152252 Hom.: 0 Cov.: 32

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

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

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

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:13 Benign:1 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 29, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 31, 2023	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) -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

COACH syndrome 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 26, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -

Meckel syndrome, type 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 15, 2023

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. -

RHYNS syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Oct 02, 2019

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

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

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 condition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 09, 2023

The TMEM67 c.958A>T variant is predicted to result in the amino acid substitution p.Ser320Cys. The TMEM67 c.653G>C and c.958A>T variants have been reported in cis phase in a patient with Bardet-Biedl syndrome who was homozygous for a 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 (http://gnomad.broadinstitute.org/variant/8-94793190-A-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Joubert syndrome 6 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

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-Gruber syndrome;C0431399:Familial aplasia of the vermis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 23, 2024

- -

Bardet-Biedl syndrome 14, modifier of Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Apr 01, 2008

- -

Nephronophthisis Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

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
MutationTaster	Benign	1.0	A;A
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

Other links and lift over

dbSNP: rs111619594; hg19: chr8-94793190;