19-4282894-G-C

Variant names:

• chr19-4282894-G-C
• NM_020209.4:c.322G>C

Variant summary

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

The NM_020209.4(SHD):​c.322G>C​(p.Asp108His) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: SHD NM_020209.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.72

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHD	NM_020209.4	c.322G>C	p.Asp108His	missense_variant	Exon 2 of 6	ENST00000543264.7	NP_064594.3
SHD	NM_001372011.1	c.322G>C	p.Asp108His	missense_variant	Exon 3 of 7		NP_001358940.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHD	ENST00000543264.7	c.322G>C	p.Asp108His	missense_variant	Exon 2 of 6	1	NM_020209.4	ENSP00000446058.1
SHD	ENST00000599689.1	c.322G>C	p.Asp108His	missense_variant	Exon 2 of 5	5		ENSP00000470181.1
SHD	ENST00000593383.1	n.-189G>C		upstream_gene_variant		3		ENSP00000472139.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461872 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

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: 0.0000166

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 08, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.322G>C (p.D108H) alteration is located in exon 2 (coding exon 2) of the SHD gene. This alteration results from a G to C substitution at nucleotide position 322, causing the aspartic acid (D) at amino acid position 108 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	Uncertain	0.37
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.69	D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.7	D;.
REVEL	Benign	0.26
Sift	Uncertain	0.0010	D;.
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.67
MutPred		0.32		Loss of stability (P = 0.0877);Loss of stability (P = 0.0877);
MVP		0.85
MPC		0.65
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.75
gMVP		0.57

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-4282891;