rs16916221

Positions:

• chr8-93815432-A-C
• chr8-93815432-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_153704.6(TMEM67):​c.2892A>C​(p.Thr964Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0135 in 1,612,588 control chromosomes in the GnomAD database, including 1,672 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (200 hom., cov: 32)
  • Exomes 𝑓: 0.013 (1472 hom.)
• Consequence: TMEM67 NM_153704.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.27

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 8-93815432-A-C is Benign according to our data. Variant chr8-93815432-A-C is described in ClinVar as [Benign]. Clinvar id is 96529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-93815432-A-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.21 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM67	NM_153704.6	c.2892A>C	p.Thr964Thr	synonymous_variant	27/28	ENST00000453321.8	NP_714915.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM67	ENST00000453321.8	c.2892A>C	p.Thr964Thr	synonymous_variant	27/28	1	NM_153704.6	ENSP00000389998.3

Frequencies

GnomAD3 genomes AF: 0.0175 AC: 2669 AN: 152182 Hom.: 194 Cov.: 32

Gnomad AFR AF: 0.00241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0679

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.220

Gnomad SAS AF: 0.0579

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.0172

GnomAD3 exomes AF: 0.0408 AC: 10224 AN: 250326 Hom.: 851 AF XY: 0.0360 AC XY: 4873 AN XY: 135304

Gnomad AFR exome AF: 0.00277

Gnomad AMR exome AF: 0.130

Gnomad ASJ exome AF: 0.00507

Gnomad EAS exome AF: 0.224

Gnomad SAS exome AF: 0.0438

Gnomad FIN exome AF: 0.0000934

Gnomad NFE exome AF: 0.000635

Gnomad OTH exome AF: 0.0219

GnomAD4 exome AF: 0.0130 AC: 19001 AN: 1460288 Hom.: 1472 Cov.: 30 AF XY: 0.0133 AC XY: 9658 AN XY: 726418

Gnomad4 AFR exome AF: 0.00179

Gnomad4 AMR exome AF: 0.121

Gnomad4 ASJ exome AF: 0.00506

Gnomad4 EAS exome AF: 0.208

Gnomad4 SAS exome AF: 0.0414

Gnomad4 FIN exome AF: 0.000113

Gnomad4 NFE exome AF: 0.000408

Gnomad4 OTH exome AF: 0.0193

GnomAD4 genome AF: 0.0177 AC: 2694 AN: 152300 Hom.: 200 Cov.: 32 AF XY: 0.0206 AC XY: 1531 AN XY: 74468

Gnomad4 AFR AF: 0.00240

Gnomad4 AMR AF: 0.0686

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.220

Gnomad4 SAS AF: 0.0576

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.000720

Gnomad4 OTH AF: 0.0255

Alfa AF: 0.00160 Hom.: 3

Bravo AF: 0.0238

Asia WGS AF: 0.121 AC: 423 AN: 3474

EpiCase AF: 0.000654

EpiControl AF: 0.000771

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 05, 2013	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Meckel syndrome, type 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Nephronophthisis 11 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Joubert syndrome 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	2.4
DANN	Benign	0.75

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: rs16916221; hg19: chr8-94827660; COSMIC: COSV60037994; COSMIC: COSV60037994;