8-3219437-T-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_033225.6(CSMD1):​c.4490A>C​(p.Asn1497Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000015 in 1,330,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: CSMD1 NM_033225.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.14
• Publications: 0 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31385186).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSMD1	NM_033225.6	c.4490A>C	p.Asn1497Thr	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>C	p.Asn1497Thr	missense_variant	Exon 29 of 70	5	NM_033225.6	ENSP00000489225.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000150 AC: 2 AN: 1330064 Hom.: 0 Cov.: 29 AF XY: 0.00000154 AC XY: 1 AN XY: 651290

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: 0.00 AC: 0 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: 0.00000191 AC: 2 AN: 1047550

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.017	T;.;.;.;T;T
Eigen	Benign	-0.073
Eigen_PC	Benign	0.015
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D;.;D;D;.;D
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.31	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
PhyloP100		2.1
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.6	.;D;.;.;N;.
REVEL	Benign	0.066
Sift	Benign	0.16	.;T;.;.;D;.
Sift4G	Uncertain	0.011	D;D;D;D;D;D
Polyphen		0.071	.;.;.;.;B;B
Vest4		0.60, 0.61, 0.63, 0.68, 0.55
MutPred		0.67		.;Gain of glycosylation at N1498 (P = 0.0635);Gain of glycosylation at N1498 (P = 0.0635);.;Gain of glycosylation at N1498 (P = 0.0635);Gain of glycosylation at N1498 (P = 0.0635);
MVP		0.39
ClinPred		0.91	D
GERP RS		3.0
Varity_R		0.19
gMVP		0.23
Mutation Taster		=80/20	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;