19-16153104-C-T

Variant names:

• chr19-16153104-C-T
• NM_001382417.1:c.277C>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.277C>T​(p.Pro93Ser) 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. 14/17 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: HSH2D NM_001382417.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.05

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=0.11458248).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSH2D	NM_001382417.1	c.277C>T	p.Pro93Ser	missense_variant	Exon 4 of 6	ENST00000613986.4	NP_001369346.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSH2D	ENST00000613986.4	c.277C>T	p.Pro93Ser	missense_variant	Exon 4 of 6	2	NM_001382417.1	ENSP00000483354.1

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

May 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.277C>T (p.P93S) alteration is located in exon 6 (coding exon 3) of the HSH2D gene. This alteration results from a C to T substitution at nucleotide position 277, causing the proline (P) at amino acid position 93 to be replaced by a serine (S). 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	0.21
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	9.9
DANN	Benign	0.67
DEOGEN2	Benign	0.21	T;T;T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.50	.;T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	-0.34	N;N;.
PrimateAI	Benign	0.25	T
Sift4G	Benign	0.47	T;T;T
Polyphen		0.32	B;B;.
Vest4		0.079
MutPred		0.42		Gain of ubiquitination at K96 (P = 0.102);Gain of ubiquitination at K96 (P = 0.102);.;
MVP		0.59
ClinPred		0.14	T
GERP RS		1.1
Varity_R		0.025
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: chr19-16263914;