10-80603593-G-C

Variant names:

• chr10-80603593-G-C
• rs370850128
• NM_001388272.1:c.658G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001388272.1(SH2D4B):​c.658G>C​(p.Ala220Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A220T) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: SH2D4B NM_001388272.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.04
• Publications: 1 publications found

Genes affected

SH2D4B (HGNC:31440): (SH2 domain containing 4B) Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40804085).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001388272.1. 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
	SH2D4B	NM_001388272.1	MANE Select	c.658G>C	p.Ala220Pro	missense	Exon 5 of 8	NP_001375201.1	A0A2R8Y5Q0
	SH2D4B	NM_207372.2		c.658G>C	p.Ala220Pro	missense	Exon 5 of 7	NP_997255.2	Q5SQS7-2
	SH2D4B	NM_001145719.1		c.511G>C	p.Ala171Pro	missense	Exon 5 of 7	NP_001139191.1	Q5SQS7-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2D4B	ENST00000646907.2	MANE Select	c.658G>C	p.Ala220Pro	missense	Exon 5 of 8	ENSP00000494732.1	A0A2R8Y5Q0
	SH2D4B	ENST00000339284.6	TSL:2	c.658G>C	p.Ala220Pro	missense	Exon 5 of 7	ENSP00000345295.2	Q5SQS7-2
	SH2D4B	ENST00000313455.5	TSL:2	c.511G>C	p.Ala171Pro	missense	Exon 5 of 7	ENSP00000314242.4	Q5SQS7-3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152232 Hom.: 0 Cov.: 33

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152232 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74372

African (AFR) AF: 0.00 AC: 0 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.88	T
PhyloP100		6.0
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.20
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.020	D
Polyphen		0.97	D
Vest4		0.45
MutPred		0.26		Loss of helix (P = 0.028)
MVP		0.66
MPC		0.68
ClinPred		0.99	D
GERP RS		5.1
gMVP		0.51
Mutation Taster		=79/21	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: rs370850128; hg19: chr10-82363349;