19-35902613-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.37

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]

(HGNC:):

ACMG classification

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/exons	MANE	UniProt
HCST	NM_014266.4	c.20T>A	p.Ile7Asn	missense_variant	1/4	ENST00000246551.9
HCST	NM_001007469.2	c.20T>A	p.Ile7Asn	missense_variant	1/4
HCST	XM_017026193.2	c.20T>A	p.Ile7Asn	missense_variant	1/4
HCST	XM_047438090.1	c.20T>A	p.Ile7Asn	missense_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCST	ENST00000246551.9	c.20T>A	p.Ile7Asn	missense_variant	1/4	1	NM_014266.4	P2
HCST	ENST00000437550.2	c.20T>A	p.Ile7Asn	missense_variant	1/4	1		A2
	ENST00000624076.1	n.1243A>T		non_coding_transcript_exon_variant	1/1

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 11, 2023

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	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	21
Dann	Benign	0.97
DEOGEN2	Benign	0.38	T;.
Eigen	Benign	0.14
Eigen_PC	Benign	-0.0080
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.52	T;T
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.45	T
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	D
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.

Other links and lift over

hg19: chr19-36393515;