rs967792092

Positions:

• chr8-93786223-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_153704.6(TMEM67):​c.1289A>G​(p.Asp430Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TMEM67 NM_153704.6 missense, splice_region
• Scores: Splicing: ADA: 0.0002795
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.88

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-93786223-A-G is Pathogenic according to our data. Variant chr8-93786223-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 592161.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr8-93786223-A-G is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.3291772). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM67	NM_153704.6	c.1289A>G	p.Asp430Gly	missense_variant, splice_region_variant	13/28	ENST00000453321.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM67	ENST00000453321.8	c.1289A>G	p.Asp430Gly	missense_variant, splice_region_variant	13/28	1	NM_153704.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461398 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727004

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

RHYNS syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 04, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	16
DANN	Benign	0.46
DEOGEN2	Benign	0.30	T;T;.;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.80	T;T;T;T
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.33	T;T;T;T
MetaSVM	Uncertain	-0.056	T
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.13	N;N;N;N
REVEL	Uncertain	0.49
Sift	Benign	0.91	T;T;T;T
Sift4G	Benign	0.89	T;T;T;T
Polyphen		0.0010	.;B;.;.
Vest4		0.69, 0.41
MutPred		0.60		.;Gain of loop (P = 0.0312);.;.;
MVP		0.94
MPC		0.16
ClinPred		0.15	T
GERP RS		4.5
Varity_R		0.12
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00028
dbscSNV1_RF	Benign	0.056
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: rs967792092; hg19: chr8-94798451;