8-93785424-C-T

Variant names:

• chr8-93785424-C-T
• rs73694952
• NM_153704.6:c.1288+46C>T

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.1288+46C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.01 in 1,566,892 control chromosomes in the GnomAD database, including 1,247 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (652 hom., cov: 32)
  • Exomes 𝑓: 0.0056 (595 hom.)
• Consequence: TMEM67 NM_153704.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.180

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=-0.88).
• BP6: Variant 8-93785424-C-T is Benign according to our data. Variant chr8-93785424-C-T is described in ClinVar as [Benign]. Clinvar id is 126298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM67	NM_153704.6	c.1288+46C>T		intron_variant	Intron 12 of 27	ENST00000453321.8	NP_714915.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM67	ENST00000453321.8	c.1288+46C>T		intron_variant	Intron 12 of 27	1	NM_153704.6	ENSP00000389998.3

Frequencies

GnomAD3 genomes AF: 0.0512 AC: 7789 AN: 152008 Hom.: 648 Cov.: 32

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0241

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.0441

GnomAD3 exomes AF: 0.0139 AC: 3440 AN: 247430 Hom.: 288 AF XY: 0.0103 AC XY: 1385 AN XY: 133856

Gnomad AFR exome AF: 0.178

Gnomad AMR exome AF: 0.0109

Gnomad ASJ exome AF: 0.000502

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000470

Gnomad FIN exome AF: 0.0000494

Gnomad NFE exome AF: 0.000877

Gnomad OTH exome AF: 0.0104

GnomAD4 exome AF: 0.00559 AC: 7915 AN: 1414766 Hom.: 595 Cov.: 24 AF XY: 0.00494 AC XY: 3493 AN XY: 706620

Gnomad4 AFR exome AF: 0.183

Gnomad4 AMR exome AF: 0.0121

Gnomad4 ASJ exome AF: 0.000776

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.000638

Gnomad4 FIN exome AF: 0.0000388

Gnomad4 NFE exome AF: 0.000452

Gnomad4 OTH exome AF: 0.0139

GnomAD4 genome AF: 0.0514 AC: 7826 AN: 152126 Hom.: 652 Cov.: 32 AF XY: 0.0500 AC XY: 3718 AN XY: 74358

Gnomad4 AFR AF: 0.175

Gnomad4 AMR AF: 0.0240

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00107

Gnomad4 OTH AF: 0.0437

Alfa AF: 0.00403 Hom.: 12

Bravo AF: 0.0595

Asia WGS AF: 0.0110 AC: 39 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.0
DANN	Benign	0.48

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: rs73694952; hg19: chr8-94797652;