rs73694960

chr8-93795856-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_153704.6(TMEM67):c.1774-45A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 1,416,354 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0072 (15 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (4 hom.)
• Consequence: TMEM67 NM_153704.6 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.197

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 8-93795856-A-C is Benign according to our data. Variant chr8-93795856-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 126300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00723 (1101/152260) while in subpopulation AFR AF= 0.0216 (899/41556). AF 95% confidence interval is 0.0205. There are 15 homozygotes in gnomad4. There are 518 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM67	NM_153704.6	c.1774-45A>C		intron_variant		ENST00000453321.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM67	ENST00000453321.8	c.1774-45A>C		intron_variant		1	NM_153704.6	P1

Frequencies

GnomAD3 genomes AF: 0.00720 AC: 1096 AN: 152142 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0216

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00930

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.00765

GnomAD3 exomes AF: 0.00241 AC: 550 AN: 228654 Hom.: 4 AF XY: 0.00197 AC XY: 244 AN XY: 123964

Gnomad AFR exome AF: 0.0229

Gnomad AMR exome AF: 0.00276

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000828

Gnomad SAS exome AF: 0.00115

Gnomad FIN exome AF: 0.0000954

Gnomad NFE exome AF: 0.000549

Gnomad OTH exome AF: 0.00204

GnomAD4 exome AF: 0.00106 AC: 1336 AN: 1264094 Hom.: 4 Cov.: 17 AF XY: 0.000969 AC XY: 618 AN XY: 637610

Gnomad4 AFR exome AF: 0.0224

Gnomad4 AMR exome AF: 0.00322

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000310

Gnomad4 SAS exome AF: 0.000741

Gnomad4 FIN exome AF: 0.0000569

Gnomad4 NFE exome AF: 0.000406

Gnomad4 OTH exome AF: 0.00234

GnomAD4 genome AF: 0.00723 AC: 1101 AN: 152260 Hom.: 15 Cov.: 32 AF XY: 0.00696 AC XY: 518 AN XY: 74450

Gnomad4 AFR AF: 0.0216

Gnomad4 AMR AF: 0.00935

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.00383 Hom.: 1

Bravo AF: 0.00864

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 06, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.51
Dann	Benign	0.15

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: rs73694960; hg19: chr8-94808084; COSMIC: COSV60038688; COSMIC: COSV60038688;