rs35765535

chr8-93786243-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1 BP4_Strong BP6

The NM_153704.6(TMEM67):c.1309C>G(p.Leu437Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00311 in 1,613,922 control chromosomes in the GnomAD database, including 9 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 0.0021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (9 hom.)
• Consequence: TMEM67 NM_153704.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 2.25

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 -3 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_153704.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.018277079).
• BP6: Variant 8-93786243-C-G is Benign according to our data. Variant chr8-93786243-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 126299.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=6}. Variant chr8-93786243-C-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM67	NM_153704.6	c.1309C>G	p.Leu437Val	missense_variant	13/28	ENST00000453321.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM67	ENST00000453321.8	c.1309C>G	p.Leu437Val	missense_variant	13/28	1	NM_153704.6	P1

Frequencies

GnomAD3 genomes AF: 0.00207 AC: 315 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00368

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00297

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00201 AC: 504 AN: 251080 Hom.: 1 AF XY: 0.00200 AC XY: 271 AN XY: 135748

Gnomad AFR exome AF: 0.000680

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000719

Gnomad FIN exome AF: 0.00264

Gnomad NFE exome AF: 0.00305

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00322 AC: 4712 AN: 1461664 Hom.: 9 Cov.: 31 AF XY: 0.00311 AC XY: 2264 AN XY: 727158

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.00165

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000661

Gnomad4 FIN exome AF: 0.00277

Gnomad4 NFE exome AF: 0.00383

Gnomad4 OTH exome AF: 0.00245

GnomAD4 genome AF: 0.00207 AC: 315 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.00230 AC XY: 171 AN XY: 74442

Gnomad4 AFR AF: 0.000770

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00368

Gnomad4 NFE AF: 0.00297

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00270 Hom.: 2

Bravo AF: 0.00207

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00267 AC: 23

ExAC AF: 0.00188 AC: 228

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 18, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 26, 2022	Variant summary: TMEM67 c.1309C>G (p.Leu437Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.002 in 251080 control chromosomes, predominantly at a frequency of 0.0031 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.75 fold of the estimated maximal expected allele frequency for a pathogenic variant in TMEM67 causing Joubert Syndrome And Related Disorders phenotype (0.0018), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Although reported in the literature, to our knowledge, no penetrant association of c.1309C>G in individuals affected with Joubert Syndrome And Related Disorders has been reported. At least one publication reports experimental evidence evaluating an impact on protein function (example, Leitch_2008). These results showed no damaging effect of this variant. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=2; VUS, n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 15, 2021	This variant is associated with the following publications: (PMID: 19574260) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	TMEM67: BS2 -

Meckel syndrome, type 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant 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 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Pathogenic	0.18
Cadd	Benign	17
Dann	Uncertain	1.0
DEOGEN2	Benign	0.27	T;T;.;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.015
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.018	T;T;T;T
MetaSVM	Uncertain	0.39	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.61	N;N;N;N
REVEL	Uncertain	0.53
Sift	Benign	0.19	T;T;T;D
Sift4G	Uncertain	0.035	D;T;T;T
Polyphen		0.026	.;B;.;.
Vest4		0.79, 0.77
MVP		0.97
MPC		0.12
ClinPred		0.015	T
GERP RS		4.8
Varity_R		0.14
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.20		Position offset: -20

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

Publications

LitVar

Other links and lift over

dbSNP: rs35765535; hg19: chr8-94798471;