21-40044143-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4 BS2

The NM_001389.5(DSCAM):c.5318C>A(p.Pro1773His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,858 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: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: DSCAM NM_001389.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.84

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 Likely_benign. Variant got -4 ACMG points.

• PP2: Missense variant where missense usually causes diseases, DSCAM
• BP4: Computational evidence support a benign effect (MetaRNN=0.3978083).
• BS2: High AC in GnomAdExome at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSCAM	NM_001389.5	c.5318C>A	p.Pro1773His	missense_variant	31/33	ENST00000400454.6
DSCAM	NM_001271534.3	c.5318C>A	p.Pro1773His	missense_variant	31/33
DSCAM	XM_017028281.2	c.4610C>A	p.Pro1537His	missense_variant	28/30
DSCAM	NR_073202.3	n.5624C>A		non_coding_transcript_exon_variant	31/33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSCAM	ENST00000400454.6	c.5318C>A	p.Pro1773His	missense_variant	31/33	1	NM_001389.5	P1
DSCAM	ENST00000404019.2	c.4574C>A	p.Pro1525His	missense_variant	27/29	1
DSCAM	ENST00000617870.4	c.4823C>A	p.Pro1608His	missense_variant	28/30	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000240 AC: 6 AN: 249618 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 135406

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461858 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 727224

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: 0.000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000247 AC: 3

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

Jul 09, 2021

The c.5318C>A (p.P1773H) alteration is located in exon 31 (coding exon 31) of the DSCAM gene. This alteration results from a C to A substitution at nucleotide position 5318, causing the proline (P) at amino acid position 1773 to be replaced by a histidine (H). 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	Uncertain	0.017	T
BayesDel_noAF	Uncertain	0.060
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.15	T;.;.
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.40	T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.90	L;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.4	N;.;N
REVEL	Benign	0.22
Sift	Uncertain	0.0090	D;.;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.83
MutPred		0.17		Gain of MoRF binding (P = 0.0646);.;.;
MVP		0.71
MPC		1.5
ClinPred		0.57	D
GERP RS		5.5
Varity_R		0.27
gMVP		0.58

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: rs767371034; hg19: chr21-41416070;