19-4283173-G-C

Variant names:

• chr19-4283173-G-C
• rs1769377052
• NM_020209.4:c.523G>C

Variant summary

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

The NM_020209.4(SHD):​c.523G>C​(p.Glu175Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SHD NM_020209.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.67

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39959276).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHD	NM_020209.4	c.523G>C	p.Glu175Gln	missense_variant	Exon 3 of 6	ENST00000543264.7	NP_064594.3
SHD	NM_001372011.1	c.523G>C	p.Glu175Gln	missense_variant	Exon 4 of 7		NP_001358940.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHD	ENST00000543264.7	c.523G>C	p.Glu175Gln	missense_variant	Exon 3 of 6	1	NM_020209.4	ENSP00000446058.1
SHD	ENST00000599689.1	c.523G>C	p.Glu175Gln	missense_variant	Exon 3 of 5	5		ENSP00000470181.1
SHD	ENST00000593383.1	n.91G>C		non_coding_transcript_exon_variant	Exon 1 of 4	3		ENSP00000472139.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461848 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727218

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.523G>C (p.E175Q) alteration is located in exon 3 (coding exon 3) of the SHD gene. This alteration results from a G to C substitution at nucleotide position 523, causing the glutamic acid (E) at amino acid position 175 to be replaced by a glutamine (Q). 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	0.25
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.40	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.2	N;.
REVEL	Benign	0.21
Sift	Benign	0.097	T;.
Sift4G	Uncertain	0.026	D;D
Polyphen		0.62	P;.
Vest4		0.45
MutPred		0.14		Gain of MoRF binding (P = 0.4507);Gain of MoRF binding (P = 0.4507);
MVP		0.65
MPC		0.32
ClinPred		0.97	D
GERP RS		5.5
Varity_R		0.27
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1769377052; hg19: chr19-4283170;