21-40044069-A-T

Position:

• chr21-40044069-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001389.5(DSCAM):​c.5383+9T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,613,010 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (7 hom.)
• Consequence: DSCAM NM_001389.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.23

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 21-40044069-A-T is Benign according to our data. Variant chr21-40044069-A-T is described in ClinVar as [Benign]. Clinvar id is 787505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00103 (1504/1460684) while in subpopulation MID AF= 0.0222 (108/4866). AF 95% confidence interval is 0.0188. There are 7 homozygotes in gnomad4_exome. There are 744 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 332 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSCAM	NM_001389.5	c.5383+9T>A		intron_variant		ENST00000400454.6	NP_001380.2
DSCAM	NM_001271534.3	c.5383+9T>A		intron_variant			NP_001258463.1
DSCAM	XM_017028281.2	c.4675+9T>A		intron_variant			XP_016883770.1
DSCAM	NR_073202.3	n.5689+9T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSCAM	ENST00000400454.6	c.5383+9T>A		intron_variant		1	NM_001389.5	ENSP00000383303	P1
DSCAM	ENST00000404019.2	c.4639+9T>A		intron_variant		1		ENSP00000385342
DSCAM	ENST00000617870.4	c.4888+9T>A		intron_variant		5		ENSP00000478698

Frequencies

GnomAD3 genomes AF: 0.00218 AC: 332 AN: 152208 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00407

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00152 AC: 378 AN: 249234 Hom.: 3 AF XY: 0.00146 AC XY: 197 AN XY: 135162

Gnomad AFR exome AF: 0.00412

Gnomad AMR exome AF: 0.00284

Gnomad ASJ exome AF: 0.000895

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000883

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00135

Gnomad OTH exome AF: 0.00446

GnomAD4 exome AF: 0.00103 AC: 1504 AN: 1460684 Hom.: 7 Cov.: 31 AF XY: 0.00102 AC XY: 744 AN XY: 726638

Gnomad4 AFR exome AF: 0.00469

Gnomad4 AMR exome AF: 0.00273

Gnomad4 ASJ exome AF: 0.000651

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000685

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000825

Gnomad4 OTH exome AF: 0.00206

GnomAD4 genome AF: 0.00218 AC: 332 AN: 152326 Hom.: 2 Cov.: 33 AF XY: 0.00224 AC XY: 167 AN XY: 74498

Gnomad4 AFR AF: 0.00406

Gnomad4 AMR AF: 0.00379

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00104

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00197 Hom.: 1

Bravo AF: 0.00247

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00185

EpiControl AF: 0.00213

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

DSCAM-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 21, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.4
DANN	Benign	0.47

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: rs200011504; hg19: chr21-41415996;