21-40042661-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001389.5(DSCAM):c.5396G>A(p.Ser1799Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000771 in 1,296,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: DSCAM NM_001389.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.37

Genes affected

DSCAM (HGNC:3039): (DS cell adhesion molecule) This gene is a member of the immunoglobulin superfamily of cell adhesion molecules (Ig-CAMs), and is involved in human central and peripheral nervous system development. This gene is a candidate for Down syndrome and congenital heart disease (DSCHD). A gene encoding a similar Ig-CAM protein is located on chromosome 11. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Oct 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, DSCAM
• BP4: Computational evidence support a benign effect (MetaRNN=0.19837171).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSCAM	NM_001389.5	c.5396G>A	p.Ser1799Asn	missense_variant	32/33	ENST00000400454.6
DSCAM	NM_001271534.3	c.5396G>A	p.Ser1799Asn	missense_variant	32/33
DSCAM	XM_017028281.2	c.4688G>A	p.Ser1563Asn	missense_variant	29/30
DSCAM	NR_073202.3	n.5702G>A		non_coding_transcript_exon_variant	32/33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSCAM	ENST00000400454.6	c.5396G>A	p.Ser1799Asn	missense_variant	32/33	1	NM_001389.5	P1
DSCAM	ENST00000404019.2	c.4652G>A	p.Ser1551Asn	missense_variant	28/29	1
DSCAM	ENST00000617870.4	c.4901G>A	p.Ser1634Asn	missense_variant	29/30	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.71e-7 AC: 1 AN: 1296242 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 634744

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: 9.80e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 28, 2022

The c.5396G>A (p.S1799N) alteration is located in exon 32 (coding exon 32) of the DSCAM gene. This alteration results from a G to A substitution at nucleotide position 5396, causing the serine (S) at amino acid position 1799 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	0.18
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
Cadd	Uncertain	25
Dann	Benign	0.50
DEOGEN2	Benign	0.044	T;.;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.90	L;.;.
MutationTaster	Benign	0.94	D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	1.2	N;.;N
REVEL	Benign	0.18
Sift	Benign	1.0	T;.;T
Sift4G	Benign	0.78	T;T;T
Polyphen		0.99	D;.;.
Vest4		0.33
MutPred		0.13		Loss of phosphorylation at S1799 (P = 0.0017);.;.;
MVP		0.65
MPC		0.50
ClinPred		0.76	D
GERP RS		5.3
Varity_R		0.15
gMVP		0.65

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

Other links and lift over

dbSNP: rs2088774781; hg19: chr21-41414588;