20-45327330-T-G

Variant names:

• chr20-45327330-T-G
• NM_002999.4:c.531A>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002999.4(SDC4):​c.531A>C​(p.Glu177Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SDC4 NM_002999.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.103

Genes affected

SDC4 (HGNC:10661): (syndecan 4) The protein encoded by this gene is a transmembrane (type I) heparan sulfate proteoglycan that functions as a receptor in intracellular signaling. The encoded protein is found as a homodimer and is a member of the syndecan proteoglycan family. This gene is found on chromosome 20, while a pseudogene has been found on chromosome 22. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.787

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDC4	NM_002999.4	c.531A>C	p.Glu177Asp	missense_variant	Exon 5 of 5	ENST00000372733.3	NP_002990.2
SDC4	XM_011528977.3	c.315A>C	p.Glu105Asp	missense_variant	Exon 4 of 4		XP_011527279.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDC4	ENST00000372733.3	c.531A>C	p.Glu177Asp	missense_variant	Exon 5 of 5	1	NM_002999.4	ENSP00000361818.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 18, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.531A>C (p.E177D) alteration is located in exon 5 (coding exon 5) of the SDC4 gene. This alteration results from a A to C substitution at nucleotide position 531, causing the glutamic acid (E) at amino acid position 177 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	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Benign	0.027
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.5	M
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.50		Loss of ubiquitination at K173 (P = 0.0744);
MVP		0.77
MPC		0.43
ClinPred		0.97	D
GERP RS		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.78
gMVP		0.53

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-43955970;