17-7356232-A-T

Variant names:

• chr17-7356232-A-T
• NM_001320436.2:c.365A>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001320436.2(TMEM95):​c.365A>T​(p.Lys122Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TMEM95 NM_001320436.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.432

Genes affected

TMEM95 (HGNC:27898): (transmembrane protein 95) Predicted to be involved in fusion of sperm to egg plasma membrane involved in single fertilization. Predicted to be located in sperm plasma membrane. Predicted to be integral component of membrane. Predicted to be active in acrosomal membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.097010046).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM95	NM_001320436.2	c.365A>T	p.Lys122Met	missense_variant	Exon 5 of 7	ENST00000576060.6	NP_001307365.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM95	ENST00000576060.6	c.365A>T	p.Lys122Met	missense_variant	Exon 5 of 7	1	NM_001320436.2	ENSP00000460828.1
TMEM95	ENST00000389982.8	c.365A>T	p.Lys122Met	missense_variant	Exon 5 of 7	1		ENSP00000374632.4
TMEM95	ENST00000330767.4	c.389A>T	p.Lys130Met	missense_variant	Exon 5 of 7	1		ENSP00000331466.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.389A>T (p.K130M) alteration is located in exon 5 (coding exon 5) of the TMEM95 gene. This alteration results from a A to T substitution at nucleotide position 389, causing the lysine (K) at amino acid position 130 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	8.3
DANN	Benign	0.76
DEOGEN2	Benign	0.19	.;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.62	T;T;T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.097	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N;N;.
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-3.0	D;.;D
REVEL	Benign	0.070
Sift	Uncertain	0.0050	D;.;D
Sift4G	Uncertain	0.014	D;D;D
Polyphen		0.79	P;B;B
Vest4		0.36
MutPred		0.27		Loss of methylation at K122 (P = 0.003);Loss of methylation at K122 (P = 0.003);.;
MVP		0.072
MPC		0.040
ClinPred		0.46	T
GERP RS		-6.6
Varity_R		0.091
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-7259551;