rs73694924

chr8-93763989-G-A

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.506+48G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00362 in 1,170,268 control chromosomes in the GnomAD database, including 110 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (71 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (39 hom.)
• Consequence: TMEM67 NM_153704.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0930

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=-0.98).
• BP6: Variant 8-93763989-G-A is Benign according to our data. Variant chr8-93763989-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 262753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0521 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM67	NM_153704.6	c.506+48G>A		intron_variant		ENST00000453321.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM67	ENST00000453321.8	c.506+48G>A		intron_variant		1	NM_153704.6	P1

Frequencies

GnomAD3 genomes AF: 0.0161 AC: 2452 AN: 152116 Hom.: 71 Cov.: 32

Gnomad AFR AF: 0.0537

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0117

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.0167

GnomAD3 exomes AF: 0.00413 AC: 967 AN: 234324 Hom.: 22 AF XY: 0.00320 AC XY: 406 AN XY: 126792

Gnomad AFR exome AF: 0.0554

Gnomad AMR exome AF: 0.00361

Gnomad ASJ exome AF: 0.000510

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000104

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000126

Gnomad OTH exome AF: 0.00224

GnomAD4 exome AF: 0.00174 AC: 1771 AN: 1018034 Hom.: 39 Cov.: 14 AF XY: 0.00147 AC XY: 773 AN XY: 526022

Gnomad4 AFR exome AF: 0.0537

Gnomad4 AMR exome AF: 0.00434

Gnomad4 ASJ exome AF: 0.000733

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000144

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000619

Gnomad4 OTH exome AF: 0.00445

GnomAD4 genome AF: 0.0162 AC: 2467 AN: 152234 Hom.: 71 Cov.: 32 AF XY: 0.0158 AC XY: 1176 AN XY: 74424

Gnomad4 AFR AF: 0.0539

Gnomad4 AMR AF: 0.0116

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.00870 Hom.: 8

Bravo AF: 0.0189

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 16, 2018

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	-0.98
Cadd	Benign	0.29
Dann	Benign	0.16

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: rs73694924; hg19: chr8-94776217;