19-4280265-G-C

Variant names:

• chr19-4280265-G-C
• rs1971243883
• NM_020209.4:c.202G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020209.4(SHD):​c.202G>C​(p.Asp68His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,236 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SHD NM_020209.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.68

Genes affected

SHD (HGNC:30633): (Src homology 2 domain containing transforming protein D) Predicted to enable phosphotyrosine residue binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13332185).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHD	NM_020209.4	c.202G>C	p.Asp68His	missense_variant	Exon 1 of 6	ENST00000543264.7	NP_064594.3
SHD	NM_001372011.1	c.202G>C	p.Asp68His	missense_variant	Exon 2 of 7		NP_001358940.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHD	ENST00000543264.7	c.202G>C	p.Asp68His	missense_variant	Exon 1 of 6	1	NM_020209.4	ENSP00000446058.1
SHD	ENST00000599689.1	c.202G>C	p.Asp68His	missense_variant	Exon 1 of 5	5		ENSP00000470181.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461236 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 726912

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.202G>C (p.D68H) alteration is located in exon 1 (coding exon 1) of the SHD gene. This alteration results from a G to C substitution at nucleotide position 202, causing the aspartic acid (D) at amino acid position 68 to be replaced by a histidine (H). 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	0.14
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.21	T;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.4	N;.
REVEL	Benign	0.061
Sift	Benign	0.032	D;.
Sift4G	Benign	0.10	T;T
Polyphen		0.64	P;.
Vest4		0.15
MutPred		0.15		Gain of MoRF binding (P = 0.0536);Gain of MoRF binding (P = 0.0536);
MVP		0.70
MPC		0.62
ClinPred		0.59	D
GERP RS		2.3
Varity_R		0.12
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1971243883; hg19: chr19-4280262;