15-78098587-A-C

Position:

• chr15-78098587-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001101404.2(SH2D7):​c.636A>C​(p.Glu212Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,294 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SH2D7 NM_001101404.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.496

Genes affected

SH2D7 (HGNC:34549): (SH2 domain containing 7)

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.045417756).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SH2D7	NM_001101404.2	c.636A>C	p.Glu212Asp	missense_variant	4/6	ENST00000328828.6	NP_001094874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SH2D7	ENST00000328828.6	c.636A>C	p.Glu212Asp	missense_variant	4/6	5	NM_001101404.2	ENSP00000327846.5
SH2D7	ENST00000409568.6	c.228A>C	p.Glu76Asp	missense_variant	4/6	5		ENSP00000386676.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461294 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726882

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 22, 2024

The c.636A>C (p.E212D) alteration is located in exon 4 (coding exon 4) of the SH2D7 gene. This alteration results from a A to C substitution at nucleotide position 636, causing the glutamic acid (E) at amino acid position 212 to be replaced by an aspartic acid (D). 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	0.086
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	3.6
DANN	Benign	0.83
DEOGEN2	Benign	0.0072	.;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0075	N
LIST_S2	Benign	0.41	T;T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.045	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.6	.;L
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.039
Sift	Benign	0.30	T;T
Sift4G	Benign	0.16	T;T
Polyphen		0.0010	.;B
Vest4		0.10
MutPred		0.14		.;Loss of helix (P = 0.1299);
MVP		0.15
MPC		0.037
ClinPred		0.10	T
GERP RS		-7.3
Varity_R		0.049
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2073991237; hg19: chr15-78390929;