17-44014391-A-T

Position:

• chr17-44014391-A-T

Variant summary

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

The NM_032376.4(TMEM101):​c.284T>A​(p.Ile95Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMEM101 NM_032376.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.15

Genes affected

TMEM101 (HGNC:28653): (transmembrane protein 101) Involved in positive regulation of I-kappaB kinase/NF-kappaB signaling. Predicted to be integral component of 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=0.19426426).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM101	NM_032376.4	c.284T>A	p.Ile95Asn	missense_variant	2/4	ENST00000206380.8	NP_115752.1
TMEM101	NM_001304813.2	c.110T>A	p.Ile37Asn	missense_variant	3/5		NP_001291742.1
TMEM101	NM_001304814.2	c.110T>A	p.Ile37Asn	missense_variant	3/5		NP_001291743.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM101	ENST00000206380.8	c.284T>A	p.Ile95Asn	missense_variant	2/4	1	NM_032376.4	ENSP00000206380	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000623 AC: 1 AN: 160424 Hom.: 0 AF XY: 0.0000118 AC XY: 1 AN XY: 84898

Gnomad AFR exome AF: 0.000111

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.000111 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 10, 2022

The c.284T>A (p.I95N) alteration is located in exon 2 (coding exon 2) of the TMEM101 gene. This alteration results from a T to A substitution at nucleotide position 284, causing the isoleucine (I) at amino acid position 95 to be replaced by an asparagine (N). 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	0.31
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.064	T;T;T;.;.;.
Eigen	Benign	0.092
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.89	.;D;D;D;D;D
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.19	T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.55	N;N;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.9	.;N;.;.;.;.
REVEL	Benign	0.062
Sift	Uncertain	0.021	.;D;.;.;.;.
Sift4G	Uncertain	0.015	D;D;D;D;.;.
Polyphen		0.52	P;P;.;.;.;.
Vest4		0.37
MutPred		0.43		Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);.;.;.;
MVP		0.20
MPC		0.82
ClinPred		0.57	D
GERP RS		4.8
Varity_R		0.38
gMVP		0.81

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: rs1567946997; hg19: chr17-42091759;