Genetic Variant NM_014266.4:c.20T>A (chr19-35902613-T-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_014266.4(HCST):c.20T>A(p.Ile7Asn) 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 pathogenic outcome for this variant. 11/19 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

HCST
NM_014266.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.37

Variant links:

Genes affected

HCST (HGNC:16977): (hematopoietic cell signal transducer) This gene encodes a transmembrane signaling adaptor that contains a YxxM motif in its cytoplasmic domain. The encoded protein may form part of the immune recognition receptor complex with the C-type lectin-like receptor NKG2D. As part of this receptor complex, this protein may activate phosphatidylinositol 3-kinase dependent signaling pathways through its intracytoplasmic YxxM motif. This receptor complex may have a role in cell survival and proliferation by activation of NK and T cell responses. Alternative splicing results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

HCST links:

ENSG00000280194 (HGNC:):

ENSG00000280194 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.816

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCST	NM_014266.4 link	c.20T>A	p.Ile7Asn	missense_variant	Exon 1 of 4	ENST00000246551.9	NP_055081.1	Q9UBK5-1
HCST	NM_001007469.2 link	c.20T>A	p.Ile7Asn	missense_variant	Exon 1 of 4		NP_001007470.1	Q9UBK5-2
HCST	XM_017026193.2 link	c.20T>A	p.Ile7Asn	missense_variant	Exon 1 of 4		XP_016881682.1
HCST	XM_047438090.1 link	c.20T>A	p.Ile7Asn	missense_variant	Exon 1 of 4		XP_047294046.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HCST	ENST00000246551.9 link	c.20T>A	p.Ile7Asn	missense_variant	Exon 1 of 4	1	NM_014266.4	ENSP00000246551.3	Q9UBK5-1
HCST	ENST00000437550.2 link	c.20T>A	p.Ile7Asn	missense_variant	Exon 1 of 4	1		ENSP00000400516.1	Q9UBK5-2
ENSG00000280194	ENST00000624076.1 link	n.1243A>T		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 11, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.20T>A (p.I7N) alteration is located in exon 1 (coding exon 1) of the HCST gene. This alteration results from a T to A substitution at nucleotide position 20, causing the isoleucine (I) at amino acid position 7 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

0.33

BayesDel_addAF

Benign

-0.014

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.38

T;.

Eigen

Benign

0.14

Eigen_PC

Benign

-0.0080

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.52

T;T

M_CAP

Benign

0.018

MetaRNN

Pathogenic

0.82

D;D

MetaSVM

Benign

-0.92

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-3.3

D;D

REVEL

Uncertain

0.30

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

0.99

D;D

Vest4

0.71

MutPred

0.66

Gain of loop (P = 0.0121);Gain of loop (P = 0.0121);

MVP

0.48

MPC

1.1

ClinPred

0.93

GERP RS

3.7

Varity_R

0.53

gMVP

0.77

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over