12-57456602-G-T

Position:

• chr12-57456602-G-T

Variant summary

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

The NM_031479.5(INHBE):​c.807G>T​(p.Glu269Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: INHBE NM_031479.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.05

Genes affected

INHBE (HGNC:24029): (inhibin subunit beta E) This gene encodes a member of the TGF-beta (transforming growth factor-beta) superfamily of proteins. The encoded preproprotein is proteolytically processed to generate an inhibin beta subunit. Inhibins have been implicated in regulating numerous cellular processes including cell proliferation, apoptosis, immune response and hormone secretion. This gene may be upregulated under conditions of endoplasmic reticulum stress, and this protein may inhibit cellular proliferation and growth in pancreas and liver. [provided by RefSeq, Sep 2016]

INHBE (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INHBE	NM_031479.5	c.807G>T	p.Glu269Asp	missense_variant	2/2	ENST00000266646.3	NP_113667.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INHBE	ENST00000266646.3	c.807G>T	p.Glu269Asp	missense_variant	2/2	1	NM_031479.5	ENSP00000266646.2
INHBE	ENST00000551553.1	n.726G>T		non_coding_transcript_exon_variant	2/3	1
INHBE	ENST00000547970.1	n.876G>T		non_coding_transcript_exon_variant	3/3	3
INHBE	ENST00000553033.1	n.533G>T		non_coding_transcript_exon_variant	2/2	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Dec 27, 2023

The c.807G>T (p.E269D) alteration is located in exon 2 (coding exon 2) of the INHBE gene. This alteration results from a G to T substitution at nucleotide position 807, causing the glutamic acid (E) at amino acid position 269 to be replaced by an aspartic acid (D). 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	0.18
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	.;D
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.5	.;L
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.7	N;N
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.029	D;T
Polyphen		0.27	.;B
Vest4		0.34
MutPred		0.46		.;Gain of catalytic residue at N274 (P = 2e-04);
MVP		0.95
MPC		0.85
ClinPred		0.96	D
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.58
gMVP		0.67

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: rs779157178; hg19: chr12-57850385;