19-16157469-C-T

Variant names:

• chr19-16157469-C-T
• NM_001382417.1:c.734C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001382417.1(HSH2D):​c.734C>T​(p.Pro245Leu) 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 benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: HSH2D NM_001382417.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.46

Genes affected

HSH2D (HGNC:24920): (hematopoietic SH2 domain containing) T-cell activation requires 2 signals: recognition of antigen by the T-cell receptor (see TCR; MIM 186880) and a costimulatory signal provided primarily by CD28 (MIM 186760) in naive T cells. HSH2 is a target of both of these signaling pathways (Greene et al., 2003 [PubMed 12960172]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1257908).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSH2D	NM_001382417.1	c.734C>T	p.Pro245Leu	missense_variant	Exon 6 of 6	ENST00000613986.4	NP_001369346.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSH2D	ENST00000613986.4	c.734C>T	p.Pro245Leu	missense_variant	Exon 6 of 6	2	NM_001382417.1	ENSP00000483354.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.734C>T (p.P245L) alteration is located in exon 8 (coding exon 5) of the HSH2D gene. This alteration results from a C to T substitution at nucleotide position 734, causing the proline (P) at amino acid position 245 to be replaced by a leucine (L). 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	0.084
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T;T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.53	.;T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.98	T
PrimateAI	Benign	0.23	T
Sift4G	Uncertain	0.054	T;T
Polyphen		0.82	P;P
Vest4		0.060
MutPred		0.26		Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);
MVP		0.47
ClinPred		0.70	D
GERP RS		2.4
Varity_R		0.10
gMVP		0.13

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: chr19-16268280;