Genetic Variant TMEM67:p.Gly75Val (chr8-93755778-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_153704.6(TMEM67):c.224G>T(p.Gly75Val) variant causes a missense, splice region change. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000016 ( 0 hom., cov: 26)

Exomes 𝑓: 0.00013 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TMEM67
NM_153704.6 missense, splice_region

Scores

Splicing: ADA: 0.9995

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.51

Variant links:

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]

TMEM67 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM67	NM_153704.6 link	c.224G>T	p.Gly75Val	missense_variant, splice_region_variant	Exon 2 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.224G>T	p.Gly75Val	missense_variant, splice_region_variant	Exon 2 of 28	1	NM_153704.6	ENSP00000389998.3		Q5HYA8

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

123304

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.0000649

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000132

AC:

AN:

680764

Hom.:

Cov.:

AF XY:

0.000115

AC XY:

AN XY:

355970

show subpopulations

Gnomad4 AFR exome

AF:

0.000133

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000605

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000589

Gnomad4 FIN exome

AF:

0.0000226

Gnomad4 NFE exome

AF:

0.000171

Gnomad4 OTH exome

AF:

0.0000656

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000162

AC:

AN:

123304

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

58232

show subpopulations

Gnomad4 AFR

AF:

0.0000649

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

T;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.84

T;T

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.77

D;D

MetaSVM

Uncertain

0.63

MutationAssessor

Pathogenic

2.9

M;.

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-3.8

D;D

REVEL

Pathogenic

0.70

Sift

Benign

0.034

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

0.99

D;.

Vest4

0.79

MutPred

0.49

Loss of disorder (P = 0.0653);Loss of disorder (P = 0.0653);

MVP

1.0

MPC

0.62

ClinPred

0.99

GERP RS

5.9

Varity_R

0.48

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.80

SpliceAI score (max)

0.35

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.35

Position offset: 24

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over