9-37919925-C-A

Variant names:

• chr9-37919925-C-A
• rs377422700
• NM_003028.3:c.1426G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003028.3(SHB):​c.1426G>T​(p.Asp476Tyr) 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 pathogenic 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. D476N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SHB NM_003028.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.03
• Publications: 1 publications found

Genes affected

SHB (HGNC:10838): (SH2 domain containing adaptor protein B) Enables phosphotyrosine residue binding activity. Predicted to be involved in several processes, including angiogenesis; apoptotic process; and signal transduction. Predicted to act upstream of or within several processes, including hematopoietic stem cell proliferation; negative regulation of oocyte maturation; and positive regulation of immune response. Located in cytoplasmic ribonucleoprotein granule; cytosol; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000255872 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.839

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003028.3. 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
	SHB	NM_003028.3	MANE Select	c.1426G>T	p.Asp476Tyr	missense	Exon 6 of 6	NP_003019.2	Q15464-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHB	ENST00000377707.4	TSL:1 MANE Select	c.1426G>T	p.Asp476Tyr	missense	Exon 6 of 6	ENSP00000366936.3	Q15464-1
	ENSG00000255872	ENST00000540557.1	TSL:5	n.*560-19975G>T		intron	N/A	ENSP00000457548.1
	SHB	ENST00000920838.1		c.1423G>T	p.Asp475Tyr	missense	Exon 6 of 6	ENSP00000590897.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.049	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.48	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		3.0
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Benign	0.29
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.017	D
Polyphen		0.99	D
Vest4		0.74
MVP		0.55
MPC		0.97
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.81
gMVP		0.59
Mutation Taster		=66/34	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs377422700; hg19: chr9-37919922;