8-112234441-C-A

Variant names:

• chr8-112234441-C-A
• rs754753189
• NM_198123.2:c.10664G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198123.2(CSMD3):​c.10664G>T​(p.Arg3555Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. R3555H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CSMD3 NM_198123.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.17
• Publications: 0 publications found

Genes affected

CSMD3 (HGNC:19291): (CUB and Sushi multiple domains 3) Predicted to be involved in regulation of dendrite development. Predicted to be located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

CSMD3 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09505287).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198123.2. 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
	CSMD3	NM_198123.2	MANE Select	c.10664G>T	p.Arg3555Leu	missense	Exon 68 of 71	NP_937756.1	Q7Z407-1
	CSMD3	NM_198124.2		c.10544G>T	p.Arg3515Leu	missense	Exon 69 of 72	NP_937757.1	Q7Z407-2
	CSMD3	NM_052900.3		c.10157G>T	p.Arg3386Leu	missense	Exon 66 of 69	NP_443132.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSMD3	ENST00000297405.10	TSL:1 MANE Select	c.10664G>T	p.Arg3555Leu	missense	Exon 68 of 71	ENSP00000297405.5	Q7Z407-1
	CSMD3	ENST00000343508.7	TSL:1	c.10544G>T	p.Arg3515Leu	missense	Exon 69 of 72	ENSP00000345799.3	Q7Z407-2
	CSMD3	ENST00000455883.2	TSL:1	c.10157G>T	p.Arg3386Leu	missense	Exon 66 of 69	ENSP00000412263.2	Q7Z407-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460974 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726834

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39582

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111452

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	15
DANN	Benign	0.91
DEOGEN2	Benign	0.059	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.095	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.1	N
PhyloP100		3.2
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.067
Sift	Benign	0.27	T
Sift4G	Benign	0.36	T
Polyphen		0.0	B
Vest4		0.28
MutPred		0.67		Loss of MoRF binding (P = 0.0033)
MVP		0.068
MPC		0.20
ClinPred		0.36	T
GERP RS		2.5
Varity_R		0.11
gMVP		0.36
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs754753189; hg19: chr8-113246670; COSMIC: COSV99835790;