chr19-35904144-T-C

Variant names:

• chr19-35904144-T-C
• NM_014266.4:c.266T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

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
• 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]

ACMG classification

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	c.266T>C	p.Met89Thr	missense_variant	Exon 4 of 4	ENST00000246551.9	NP_055081.1
HCST	NM_001007469.2	c.263T>C	p.Met88Thr	missense_variant	Exon 4 of 4		NP_001007470.1
HCST	XM_017026193.2	c.388T>C	p.Cys130Arg	missense_variant	Exon 4 of 4		XP_016881682.1
HCST	XM_047438090.1	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	c.266T>C	p.Met89Thr	missense_variant	Exon 4 of 4	1	NM_014266.4	ENSP00000246551.3
HCST	ENST00000437550.2	c.263T>C	p.Met88Thr	missense_variant	Exon 4 of 4	1		ENSP00000400516.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461832 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727224

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.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Uncertain	0.44	T;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.57	T;T
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.69	D;D
MetaSVM	Benign	-1.0	T
PrimateAI	Uncertain	0.68	T
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	D
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.

Other links and lift over

hg19: chr19-36395046;