Genetic Variant SHD:p.Ser168Asn (chr19-4283153-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_020209.4(SHD):c.503G>A(p.Ser168Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000192 in 1,614,026 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S168R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

SHD
NM_020209.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.63

Variant links:

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]

SHD links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 link	c.503G>A	p.Ser168Asn	missense_variant	Exon 3 of 6	ENST00000543264.7	NP_064594.3	Q96IW2
SHD	NM_001372011.1 link	c.503G>A	p.Ser168Asn	missense_variant	Exon 4 of 7		NP_001358940.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SHD	ENST00000543264.7 link	c.503G>A	p.Ser168Asn	missense_variant	Exon 3 of 6	1	NM_020209.4	ENSP00000446058.1	Q96IW2
SHD	ENST00000599689.1 link	c.503G>A	p.Ser168Asn	missense_variant	Exon 3 of 5	5		ENSP00000470181.1	M0QYZ4
SHD	ENST00000593383.1 link	n.71G>A		non_coding_transcript_exon_variant	Exon 1 of 4	3		ENSP00000472139.1	M0R1V9

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250446

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135474

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000150

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

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:

0.0000135

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.503G>A (p.S168N) alteration is located in exon 3 (coding exon 3) of the SHD gene. This alteration results from a G to A substitution at nucleotide position 503, causing the serine (S) at amino acid position 168 to be replaced by an asparagine (N). 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

Benign

-0.25

BayesDel_noAF

Benign

-0.36

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.43

T;.

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.65

T;T

M_CAP

Benign

0.054

MetaRNN

Uncertain

0.69

D;D

MetaSVM

Benign

-0.71

MutationAssessor

Uncertain

2.7

M;.

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-2.5

D;.

REVEL

Benign

0.17

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;.

Vest4

0.79

MVP

0.64

MPC

0.63

ClinPred

0.96

GERP RS

5.1

Varity_R

0.64

gMVP

0.48

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over