rs55850117

Positions:

• chr8-93816471-T-C

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.*19T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0032 in 1,442,244 control chromosomes in the GnomAD database, including 116 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: 33)
  • Exomes 𝑓: 0.0017 (45 hom.)
• Consequence: TMEM67 NM_153704.6 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0280

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=-0.84).
• BP6: Variant 8-93816471-T-C is Benign according to our data. Variant chr8-93816471-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 262739.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.052 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM67	NM_153704.6	c.*19T>C		3_prime_UTR_variant	28/28	ENST00000453321.8	NP_714915.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM67	ENST00000453321.8	c.*19T>C		3_prime_UTR_variant	28/28	1	NM_153704.6	ENSP00000389998	P1

Frequencies

GnomAD3 genomes AF: 0.0161 AC: 2450 AN: 152122 Hom.: 71 Cov.: 33

Gnomad AFR AF: 0.0537

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0116

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.0167

GnomAD3 exomes AF: 0.00418 AC: 1029 AN: 246124 Hom.: 23 AF XY: 0.00337 AC XY: 449 AN XY: 133350

Gnomad AFR exome AF: 0.0563

Gnomad AMR exome AF: 0.00355

Gnomad ASJ exome AF: 0.000505

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000681

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000125

Gnomad OTH exome AF: 0.00251

GnomAD4 exome AF: 0.00167 AC: 2148 AN: 1290004 Hom.: 45 Cov.: 18 AF XY: 0.00143 AC XY: 931 AN XY: 650488

Gnomad4 AFR exome AF: 0.0549

Gnomad4 AMR exome AF: 0.00421

Gnomad4 ASJ exome AF: 0.000724

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000124

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000532

Gnomad4 OTH exome AF: 0.00428

GnomAD4 genome AF: 0.0162 AC: 2465 AN: 152240 Hom.: 71 Cov.: 33 AF XY: 0.0158 AC XY: 1176 AN XY: 74446

Gnomad4 AFR AF: 0.0539

Gnomad4 AMR AF: 0.0115

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.0165

Alfa AF: 0.00638 Hom.: 9

Bravo AF: 0.0189

Asia WGS AF: 0.00377 AC: 13 AN: 3462

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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

Meckel syndrome, type 3 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Nephronophthisis 11 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Joubert syndrome 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	8.2
DANN	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs55850117; hg19: chr8-94828699;