11-117518745-C-G

Variant names:

• chr11-117518745-C-G
• rs759222737
• NM_020693.4:c.1231G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_020693.4(DSCAML1):​c.1231G>C​(p.Val411Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,611,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V411I) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DSCAML1 NM_020693.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.939
• Publications: 3 publications found

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]

DSCAML1 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• motor neuron disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• retinal disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• retinitis pigmentosa

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-117518745-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 402156.
• BP4: Computational evidence support a benign effect (MetaRNN=0.11725253).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020693.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSCAML1	NM_020693.4	MANE Select	c.1231G>C	p.Val411Leu	missense	Exon 7 of 33	NP_065744.3
	DSCAML1	NM_001367904.1		c.1231G>C	p.Val411Leu	missense	Exon 7 of 15	NP_001354833.1
	DSCAML1	NM_001367905.1		c.823G>C	p.Val275Leu	missense	Exon 7 of 7	NP_001354834.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSCAML1	ENST00000651296.2	MANE Select	c.1231G>C	p.Val411Leu	missense	Exon 7 of 33	ENSP00000498769.1
	DSCAML1	ENST00000321322.6	TSL:1	c.1411G>C	p.Val471Leu	missense	Exon 7 of 33	ENSP00000315465.6
	DSCAML1	ENST00000651172.1		c.1411G>C	p.Val471Leu	missense	Exon 7 of 33	ENSP00000498407.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152238 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000818 AC: 2 AN: 244382 AF XY: 0.0000151

Gnomad AFR exome AF: 0.000127

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459450 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726048

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51170

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111928

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74374

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000241 AC: 1 AN: 41470

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	20
DANN	Benign	0.97
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.51
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.94
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.027
Sift	Benign	0.79	T
Sift4G	Benign	0.90	T
Vest4		0.28
MVP		0.39
MPC		0.55
ClinPred		0.11	T
GERP RS		1.1
gMVP		0.28
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs759222737; hg19: chr11-117389460;