rs1281778614

chr8-93795448-G-Achr8-93795448-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_153704.6(TMEM67):c.1714G>A(p.Ala572Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 152,002 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: TMEM67 NM_153704.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 5.15

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM67	NM_153704.6	c.1714G>A	p.Ala572Thr	missense_variant	17/28	ENST00000453321.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM67	ENST00000453321.8	c.1714G>A	p.Ala572Thr	missense_variant	17/28	1	NM_153704.6	P1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152002 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152002 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74218

Gnomad4 AFR AF: 0.00

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: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000354 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 19, 2023

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 572 of the TMEM67 protein (p.Ala572Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 25326635). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 521968). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TMEM67 protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 26, 2021

This sequence change, c.1714G>A, in exon 17 results in an amino acid change, p.Ala572Thr. This sequence change is absent from the gnomAD population database. This sequence change does not appear to have been previously described in patients with TMEM67-related disorders. However, a different sequence change affecting the same amino acid (p.Ala572Val) has been reported in the compound heterozygous state in one autopsied fetus with bilateral enlarged cystic kidneys, ductal plate malformation in the liver and abnormal lung lobulation (PMID: 29194579). This p.Ala572Thr change affects a moderately conserved amino acid residue located in the transmembrane domain of the TMEM67 protein. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ala572Thr substitution. Due to the lack of functional studies, the clinical significance of the p.Ala572Thr change remains unknown at this time. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2017

- -

Joubert syndrome 6 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 01, 2017

This variant was found once in our laboratory in trans with another variant (F590S) in a 7-year-old female with a clinical diagnosis of Joubert syndrome. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.56	D;D
MetaSVM	Benign	-0.28	T
MutationAssessor	Uncertain	2.0	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		0.089	B;.
Vest4		0.42
MVP		1.0
MPC		0.55
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.37
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.31		Position offset: 25

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

Publications

LitVar

Other links and lift over

dbSNP: rs1281778614; hg19: chr8-94807676;