8-93755896-C-G

Variant names:

• chr8-93755896-C-G
• rs74712633
• ENST00000481620.1:n.345C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000481620.1(TMEM67):​n.345C>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00924 in 1,271,874 control chromosomes in the GnomAD database, including 130 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (11 hom., cov: 31)
  • Exomes 𝑓: 0.0096 (119 hom.)
• Consequence: TMEM67 ENST00000481620.1 non_coding_transcript_exon
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.637
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• COACH syndrome 1

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Meckel syndrome, type 3

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics
• nephronophthisis 11

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• COACH syndrome 1

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• Joubert syndrome 6

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Joubert syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Meckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Senior-Boichis syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 8-93755896-C-G is Benign according to our data. Variant chr8-93755896-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 262750.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00676 (1023/151334) while in subpopulation SAS AF = 0.028 (134/4784). AF 95% confidence interval is 0.0242. There are 11 homozygotes in GnomAd4. There are 529 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM67	NM_153704.6	c.312+30C>G		intron_variant	Intron 2 of 27	ENST00000453321.8	NP_714915.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM67	ENST00000453321.8	c.312+30C>G		intron_variant	Intron 2 of 27	1	NM_153704.6	ENSP00000389998.3

Frequencies

GnomAD3 genomes AF: 0.00675 AC: 1021 AN: 151218 Hom.: 10 Cov.: 31

Gnomad AFR AF: 0.00124

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.00501

Gnomad ASJ AF: 0.00808

Gnomad EAS AF: 0.0211

Gnomad SAS AF: 0.0280

Gnomad FIN AF: 0.00389

Gnomad MID AF: 0.0287

Gnomad NFE AF: 0.00775

Gnomad OTH AF: 0.00720

GnomAD2 exomes AF: 0.00970 AC: 2195 AN: 226180 AF XY: 0.0109

Gnomad AFR exome AF: 0.00153

Gnomad AMR exome AF: 0.00343

Gnomad ASJ exome AF: 0.00759

Gnomad EAS exome AF: 0.0252

Gnomad FIN exome AF: 0.00311

Gnomad NFE exome AF: 0.00752

Gnomad OTH exome AF: 0.00889

GnomAD4 exome AF: 0.00957 AC: 10728 AN: 1120540 Hom.: 119 Cov.: 15 AF XY: 0.0103 AC XY: 5876 AN XY: 570750

African (AFR) AF: 0.00129 AC: 34 AN: 26274

American (AMR) AF: 0.00308 AC: 129 AN: 41824

Ashkenazi Jewish (ASJ) AF: 0.00834 AC: 197 AN: 23612

East Asian (EAS) AF: 0.0295 AC: 1098 AN: 37232

South Asian (SAS) AF: 0.0278 AC: 2015 AN: 72384

European-Finnish (FIN) AF: 0.00343 AC: 178 AN: 51918

Middle Eastern (MID) AF: 0.0169 AC: 79 AN: 4682

European-Non Finnish (NFE) AF: 0.00796 AC: 6480 AN: 813988

Other (OTH) AF: 0.0107 AC: 518 AN: 48626

GnomAD4 genome AF: 0.00676 AC: 1023 AN: 151334 Hom.: 11 Cov.: 31 AF XY: 0.00716 AC XY: 529 AN XY: 73924

African (AFR) AF: 0.00124 AC: 51 AN: 41294

American (AMR) AF: 0.00501 AC: 76 AN: 15178

Ashkenazi Jewish (ASJ) AF: 0.00808 AC: 28 AN: 3466

East Asian (EAS) AF: 0.0216 AC: 111 AN: 5148

South Asian (SAS) AF: 0.0280 AC: 134 AN: 4784

European-Finnish (FIN) AF: 0.00389 AC: 40 AN: 10288

Middle Eastern (MID) AF: 0.0308 AC: 9 AN: 292

European-Non Finnish (NFE) AF: 0.00775 AC: 526 AN: 67868

Other (OTH) AF: 0.00713 AC: 15 AN: 2104

Alfa AF: 0.00752 Hom.: 1

Bravo AF: 0.00652

Asia WGS AF: 0.0270 AC: 93 AN: 3460

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 20, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.94
DANN	Benign	0.65
PhyloP100		-0.64
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs74712633; hg19: chr8-94768124; COSMIC: COSV60042625;