NM_001382417.1:c.574C>T

Variant names:

• chr19-16157309-C-T
• rs372983878
• NM_001382417.1:c.574C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001382417.1(HSH2D):​c.574C>T​(p.Pro192Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000806 in 1,613,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P192L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000084 (0 hom.)
• Consequence: HSH2D NM_001382417.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.309
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07418007).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001382417.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSH2D	NM_001382417.1	MANE Select	c.574C>T	p.Pro192Ser	missense	Exon 6 of 6	NP_001369346.1	Q96JZ2-1
	HSH2D	NM_032855.4		c.574C>T	p.Pro192Ser	missense	Exon 8 of 8	NP_116244.1	Q96JZ2-1
	HSH2D	NM_001369808.1		c.499C>T	p.Pro167Ser	missense	Exon 6 of 6	NP_001356737.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSH2D	ENST00000613986.4	TSL:2 MANE Select	c.574C>T	p.Pro192Ser	missense	Exon 6 of 6	ENSP00000483354.1	Q96JZ2-1
	HSH2D	ENST00000616645.4	TSL:1	c.574C>T	p.Pro192Ser	missense	Exon 8 of 8	ENSP00000482604.1	Q96JZ2-1
	HSH2D	ENST00000874628.1		c.574C>T	p.Pro192Ser	missense	Exon 6 of 6	ENSP00000544687.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152162 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000363 AC: 9 AN: 248136 AF XY: 0.0000297

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000800

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000835 AC: 122 AN: 1460800 Hom.: 0 Cov.: 31 AF XY: 0.0000867 AC XY: 63 AN XY: 726756

African (AFR) AF: 0.00 AC: 0 AN: 33392

American (AMR) AF: 0.00 AC: 0 AN: 44388

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86166

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000108 AC: 120 AN: 1111612

Other (OTH) AF: 0.0000166 AC: 1 AN: 60320

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152280 Hom.: 0 Cov.: 31 AF XY: 0.0000537 AC XY: 4 AN XY: 74460

African (AFR) AF: 0.00 AC: 0 AN: 41558

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68024

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000453

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.0000497 AC: 6

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	1.4
DANN	Benign	0.46
DEOGEN2	Benign	0.15	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.074	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.97	L
PhyloP100		-0.31
PrimateAI	Benign	0.20	T
Sift4G	Benign	0.70	T
Polyphen		0.51	P
Vest4		0.073
MVP		0.20
ClinPred		0.088	T
GERP RS		-3.6
Varity_R		0.049
gMVP		0.25
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs372983878; hg19: chr19-16268119;