Genetic Variant NM_014266.4:c.266T>C (chr19-35904144-T-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_014266.4(HCST):c.266T>C(p.Met89Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a mutagenesis_site Abrogates cell killing and interaction with PIK3R1. No effect on interaction with GRB2. (size 0) in uniprot entity HCST_HUMAN

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCST	NM_014266.4 link	c.266T>C	p.Met89Thr	missense_variant	Exon 4 of 4	ENST00000246551.9	NP_055081.1	Q9UBK5-1
HCST	NM_001007469.2 link	c.263T>C	p.Met88Thr	missense_variant	Exon 4 of 4		NP_001007470.1	Q9UBK5-2
HCST	XM_017026193.2 link	c.388T>C	p.Cys130Arg	missense_variant	Exon 4 of 4		XP_016881682.1
HCST	XM_047438090.1 link	c.385T>C	p.Cys129Arg	missense_variant	Exon 4 of 4		XP_047294046.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCST	ENST00000246551.9 link	c.266T>C	p.Met89Thr	missense_variant	Exon 4 of 4	1	NM_014266.4	ENSP00000246551.3		Q9UBK5-1
HCST	ENST00000437550.2 link	c.263T>C	p.Met88Thr	missense_variant	Exon 4 of 4	1		ENSP00000400516.1		Q9UBK5-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461832

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000166

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

Aug 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.266T>C (p.M89T) alteration is located in exon 4 (coding exon 4) of the HCST gene. This alteration results from a T to C substitution at nucleotide position 266, causing the methionine (M) at amino acid position 89 to be replaced by a threonine (T). 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

Pathogenic

0.85

BayesDel_addAF

Uncertain

0.053

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.44

T;.

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.57

T;T

M_CAP

Benign

0.018

MetaRNN

Uncertain

0.69

D;D

MetaSVM

Benign

-1.0

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-6.0

D;D

REVEL

Benign

0.15

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.82

P;P

Vest4

0.67

MutPred

0.66

Loss of catalytic residue at V85 (P = 0.0222);.;

MVP

0.31

MPC

0.89

ClinPred

0.97

GERP RS

3.4

Varity_R

0.74

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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