11-117428363-C-T

Position:

• chr11-117428363-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_020693.4(DSCAML1):​c.6127G>A​(p.Ala2043Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00243 in 1,583,670 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2043V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0019 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0025 (14 hom.)
• Consequence: DSCAML1 NM_020693.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.78

Genes affected

DSCAML1 (HGNC:14656): (DS cell adhesion molecule like 1) The protein encoded by this gene is a member of the Ig superfamily of cell adhesion molecules and is involved in neuronal differentiation. The encoded membrane-bound protein localizes to the cell surface, where it forms aggregates that repel neuronal processes of the same cell type. [provided by RefSeq, Sep 2016]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, DSCAML1
• BP4: Computational evidence support a benign effect (MetaRNN=0.00686422).
• BP6: Variant 11-117428363-C-T is Benign according to our data. Variant chr11-117428363-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1587898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 294 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSCAML1	NM_020693.4	c.6127G>A	p.Ala2043Thr	missense_variant	33/33	ENST00000651296.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSCAML1	ENST00000651296.2	c.6127G>A	p.Ala2043Thr	missense_variant	33/33		NM_020693.4
DSCAML1	ENST00000321322.6	c.6307G>A	p.Ala2103Thr	missense_variant	33/33	1		P1
DSCAML1	ENST00000651172.1	c.6307G>A	p.Ala2103Thr	missense_variant	33/33			P1
DSCAML1	ENST00000527706.5	c.5497G>A	p.Ala1833Thr	missense_variant	31/31	5

Frequencies

GnomAD3 genomes AF: 0.00193 AC: 293 AN: 152176 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00325

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00166 AC: 383 AN: 231238 Hom.: 2 AF XY: 0.00183 AC XY: 233 AN XY: 127126

Gnomad AFR exome AF: 0.000140

Gnomad AMR exome AF: 0.00114

Gnomad ASJ exome AF: 0.00140

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000356

Gnomad FIN exome AF: 0.000283

Gnomad NFE exome AF: 0.00296

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00248 AC: 3553 AN: 1431376 Hom.: 14 Cov.: 33 AF XY: 0.00244 AC XY: 1739 AN XY: 713128

Gnomad4 AFR exome AF: 0.000220

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.00161

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000955

Gnomad4 FIN exome AF: 0.000458

Gnomad4 NFE exome AF: 0.00296

Gnomad4 OTH exome AF: 0.00289

GnomAD4 genome AF: 0.00193 AC: 294 AN: 152294 Hom.: 2 Cov.: 31 AF XY: 0.00161 AC XY: 120 AN XY: 74476

Gnomad4 AFR AF: 0.000770

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000376

Gnomad4 NFE AF: 0.00325

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00219 Hom.: 1

Bravo AF: 0.00189

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000233 AC: 1

ESP6500EA AF: 0.00213 AC: 18

ExAC AF: 0.00156 AC: 189

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DSCAML1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 20, 2023

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

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	16
DANN	Uncertain	0.99
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.20
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.0069	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.58	N;N
REVEL	Benign	0.037
Sift	Benign	0.30	T;T
Sift4G	Benign	0.60	T;T
Vest4		0.14
MVP		0.43
MPC		0.0091
ClinPred		0.056	T
GERP RS		3.4
gMVP		0.24

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: rs143875346; hg19: chr11-117299079; COSMIC: COSV105216683;