8-3219437-T-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_033225.6(CSMD1):​c.4490A>G​(p.Asn1497Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 1,480,760 control chromosomes in the GnomAD database, including 13,111 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: 𝑓 0.11 (1172 hom., cov: 32)
  • Exomes 𝑓: 0.13 (11939 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001791805).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033225.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSMD1	NM_033225.6	MANE Select	c.4490A>G	p.Asn1497Ser	missense	Exon 29 of 70	NP_150094.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSMD1	ENST00000635120.2	TSL:5 MANE Select	c.4490A>G	p.Asn1497Ser	missense	Exon 29 of 70	ENSP00000489225.1
	CSMD1	ENST00000335551.11	TSL:1	c.2930A>G	p.Asn977Ser	missense	Exon 17 of 56	ENSP00000334828.6
	CSMD1	ENST00000523488.5	TSL:1	n.2023A>G		non_coding_transcript_exon	Exon 13 of 24

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16340 AN: 152086 Hom.: 1169 Cov.: 32

Gnomad AFR AF: 0.0271

Gnomad AMI AF: 0.0800

Gnomad AMR AF: 0.168

Gnomad ASJ AF: 0.0818

Gnomad EAS AF: 0.0518

Gnomad SAS AF: 0.0803

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.140

Gnomad OTH AF: 0.0944

GnomAD2 exomes AF: 0.127 AC: 14070 AN: 110382 AF XY: 0.127

Gnomad AFR exome AF: 0.0272

Gnomad AMR exome AF: 0.208

Gnomad ASJ exome AF: 0.0820

Gnomad EAS exome AF: 0.0528

Gnomad FIN exome AF: 0.168

Gnomad NFE exome AF: 0.136

Gnomad OTH exome AF: 0.136

GnomAD4 exome AF: 0.131 AC: 173863 AN: 1328556 Hom.: 11939 Cov.: 29 AF XY: 0.130 AC XY: 84264 AN XY: 650596

African (AFR) AF: 0.0210 AC: 595 AN: 28284

American (AMR) AF: 0.191 AC: 4213 AN: 22054

Ashkenazi Jewish (ASJ) AF: 0.0805 AC: 1690 AN: 20984

East Asian (EAS) AF: 0.0561 AC: 1933 AN: 34432

South Asian (SAS) AF: 0.0893 AC: 6179 AN: 69174

European-Finnish (FIN) AF: 0.171 AC: 8185 AN: 47944

Middle Eastern (MID) AF: 0.0959 AC: 448 AN: 4670

European-Non Finnish (NFE) AF: 0.138 AC: 144237 AN: 1046204

Other (OTH) AF: 0.116 AC: 6383 AN: 54810

GnomAD4 genome AF: 0.107 AC: 16352 AN: 152204 Hom.: 1172 Cov.: 32 AF XY: 0.109 AC XY: 8102 AN XY: 74416

African (AFR) AF: 0.0270 AC: 1123 AN: 41548

American (AMR) AF: 0.168 AC: 2569 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0818 AC: 284 AN: 3472

East Asian (EAS) AF: 0.0521 AC: 270 AN: 5178

South Asian (SAS) AF: 0.0807 AC: 389 AN: 4818

European-Finnish (FIN) AF: 0.178 AC: 1885 AN: 10592

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.140 AC: 9531 AN: 68002

Other (OTH) AF: 0.0963 AC: 203 AN: 2108

Alfa AF: 0.117 Hom.: 2212

Bravo AF: 0.102

TwinsUK AF: 0.133 AC: 495

ALSPAC AF: 0.138 AC: 530

ESP6500AA AF: 0.0263 AC: 96

ESP6500EA AF: 0.129 AC: 1058

ExAC AF: 0.0903 AC: 10420

Asia WGS AF: 0.0790 AC: 276 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	19
DANN	Benign	0.83
DEOGEN2	Benign	0.0090	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.97	T
PhyloP100		2.1
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.13
Sift	Benign	0.76	T
Sift4G	Benign	0.73	T
Polyphen		0.0	B
Vest4		0.27
ClinPred		0.0012	T
GERP RS		3.0
Varity_R		0.049
gMVP		0.15
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: -1

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

Other links and lift over

dbSNP: rs28455997; hg19: chr8-3076959; COSMIC: COSV100144442;