20-45335848-C-G

Variant names:

• chr20-45335848-C-G
• rs370755313
• NM_002999.4:c.133G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002999.4(SDC4):​c.133G>C​(p.Asp45His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D45N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SDC4 NM_002999.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.07
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002999.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDC4	NM_002999.4	MANE Select	c.133G>C	p.Asp45His	missense	Exon 2 of 5	NP_002990.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDC4	ENST00000372733.3	TSL:1 MANE Select	c.133G>C	p.Asp45His	missense	Exon 2 of 5	ENSP00000361818.3	P31431-1
	SDC4	ENST00000901705.1		c.133G>C	p.Asp45His	missense	Exon 2 of 5	ENSP00000571764.1
	SDC4	ENST00000939835.1		c.112G>C	p.Asp38His	missense	Exon 2 of 5	ENSP00000609894.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.096	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-0.60	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		4.1
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.62		Loss of disorder (P = 0.0999)
MVP		0.86
MPC		0.62
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.68
gMVP		0.57
Mutation Taster		=63/37	polymorphism

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

Other links and lift over

dbSNP: rs370755313; hg19: chr20-43964488;