chr8-93782456-A-C

Position:

• chr8-93782456-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP3_Moderate PP5

The NM_153704.6(TMEM67):​c.1127A>C​(p.Gln376Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q376E) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM67 NM_153704.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.61

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_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-93782455-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 217719.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.862
• PP5: Variant 8-93782456-A-C is Pathogenic according to our data. Variant chr8-93782456-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 1369.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr8-93782456-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM67	NM_153704.6	c.1127A>C	p.Gln376Pro	missense_variant	11/28	ENST00000453321.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM67	ENST00000453321.8	c.1127A>C	p.Gln376Pro	missense_variant	11/28	1	NM_153704.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Meckel syndrome, type 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 15, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.79	D;D;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	.;M;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-4.2	D;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.020	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.93, 0.87
MutPred		0.53		.;Gain of glycosylation at T373 (P = 0.0453);.;
MVP		1.0
MPC		0.61
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.82
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs137853106; hg19: chr8-94794684;