21-40044167-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001389.5(DSCAM):c.5294C>A(p.Thr1765Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: DSCAM NM_001389.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.70

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 2 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=0.26973218).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSCAM	NM_001389.5	c.5294C>A	p.Thr1765Asn	missense_variant	31/33	ENST00000400454.6
DSCAM	NM_001271534.3	c.5294C>A	p.Thr1765Asn	missense_variant	31/33
DSCAM	XM_017028281.2	c.4586C>A	p.Thr1529Asn	missense_variant	28/30
DSCAM	NR_073202.3	n.5600C>A		non_coding_transcript_exon_variant	31/33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSCAM	ENST00000400454.6	c.5294C>A	p.Thr1765Asn	missense_variant	31/33	1	NM_001389.5	P1
DSCAM	ENST00000404019.2	c.4550C>A	p.Thr1517Asn	missense_variant	27/29	1
DSCAM	ENST00000617870.4	c.4799C>A	p.Thr1600Asn	missense_variant	28/30	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Feb 15, 2023

The c.5294C>A (p.T1765N) 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 5294, causing the threonine (T) at amino acid position 1765 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	0.21
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.099	T;.;.
Eigen	Benign	0.082
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	0.69	N;.;.
MutationTaster	Benign	0.75	D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.0	N;.;N
REVEL	Benign	0.10
Sift	Uncertain	0.0030	D;.;D
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		0.50	P;.;.
Vest4		0.41
MutPred		0.19		Loss of glycosylation at T1765 (P = 0.0289);.;.;
MVP		0.54
MPC		1.0
ClinPred		0.93	D
GERP RS		4.7
Varity_R		0.43
gMVP		0.55

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: chr21-41416094;