9-37919952-C-A

Variant names:

• chr9-37919952-C-A
• NM_003028.3:c.1399G>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003028.3(SHB):​c.1399G>T​(p.Val467Phe) 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. 12/21 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: SHB NM_003028.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.245

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34222323).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHB	NM_003028.3	c.1399G>T	p.Val467Phe	missense_variant	Exon 6 of 6	ENST00000377707.4	NP_003019.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHB	ENST00000377707.4	c.1399G>T	p.Val467Phe	missense_variant	Exon 6 of 6	1	NM_003028.3	ENSP00000366936.3
ENSG00000255872	ENST00000540557.1	n.*560-20002G>T		intron_variant	Intron 6 of 11	5		ENSP00000457548.1

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

Oct 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1399G>T (p.V467F) alteration is located in exon 6 (coding exon 6) of the SHB gene. This alteration results from a G to T substitution at nucleotide position 1399, causing the valine (V) at amino acid position 467 to be replaced by a phenylalanine (F). 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	Uncertain	0.56
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.16	N
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.88	L
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.14
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.81	P
Vest4		0.26
MutPred		0.40		Loss of MoRF binding (P = 0.1032);
MVP		0.39
MPC		1.0
ClinPred		0.91	D
GERP RS		-6.9
Varity_R		0.20
gMVP		0.34

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: chr9-37919949;