rs28455997

Variant names:

• chr8-3219437-T-A
• rs28455997
• NM_033225.6:c.4490A>T

Your query was ambiguous. Multiple possible variants found:

• chr8-3219437-T-A
• chr8-3219437-T-C
• chr8-3219437-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_033225.6(CSMD1):​c.4490A>T​(p.Asn1497Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000135 in 1,482,168 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: CSMD1 NM_033225.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.14
• Publications: 20 publications found

Genes affected

CSMD1 (HGNC:14026): (CUB and Sushi multiple domains 1) Predicted to act upstream of or within several processes, including learning or memory; mammary gland branching involved in pregnancy; and reproductive structure development. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

CSMD1 Gene-Disease associations (from GenCC):

• autism spectrum disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• complex neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSMD1	NM_033225.6	c.4490A>T	p.Asn1497Ile	missense_variant	Exon 29 of 70	ENST00000635120.2	NP_150094.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSMD1	ENST00000635120.2	c.4490A>T	p.Asn1497Ile	missense_variant	Exon 29 of 70	5	NM_033225.6	ENSP00000489225.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152104 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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

GnomAD4 exome AF: 7.52e-7 AC: 1 AN: 1330064 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 651290

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

African (AFR) AF: 0.00 AC: 0 AN: 28286

American (AMR) AF: 0.00 AC: 0 AN: 22078

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20992

East Asian (EAS) AF: 0.00 AC: 0 AN: 34442

South Asian (SAS) AF: 0.0000144 AC: 1 AN: 69214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47978

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4678

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1047550

Other (OTH) AF: 0.00 AC: 0 AN: 54846

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152104 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74300

African (AFR) AF: 0.00 AC: 0 AN: 41432

American (AMR) AF: 0.0000655 AC: 1 AN: 15264

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 2212

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.022	T;.;.;.;T;T
Eigen	Benign	0.022
Eigen_PC	Benign	0.076
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D;.;D;D;.;D
M_CAP	Benign	0.0059	T
MetaRNN	Uncertain	0.54	D;D;D;D;D;D
MetaSVM	Benign	-0.97	T
PhyloP100		2.1
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-5.1	.;D;.;.;D;.
REVEL	Benign	0.12
Sift	Uncertain	0.0080	.;D;.;.;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		0.56	.;.;.;.;P;P
Vest4		0.88, 0.88, 0.91, 0.87, 0.86
MutPred		0.74		.;Gain of ubiquitination at K1495 (P = 0.1008);Gain of ubiquitination at K1495 (P = 0.1008);.;Gain of ubiquitination at K1495 (P = 0.1008);Gain of ubiquitination at K1495 (P = 0.1008);
MVP		0.40
ClinPred		0.99	D
GERP RS		3.0
Varity_R		0.71
gMVP		0.42
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

dbSNP: rs28455997; hg19: chr8-3076959;