rs774419933

Variant names:

• chr8-112237297-A-G
• rs774419933
• NM_198123.2:c.10520T>C

Your query was ambiguous. Multiple possible variants found:

• chr8-112237297-A-G
• chr8-112237297-A-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_198123.2(CSMD3):​c.10520T>C​(p.Phe3507Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,613,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F3507L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CSMD3 NM_198123.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.51
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.35180122).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

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.10520T>C	p.Phe3507Ser	missense	Exon 67 of 71	NP_937756.1	Q7Z407-1
	CSMD3	NM_198124.2		c.10400T>C	p.Phe3467Ser	missense	Exon 68 of 72	NP_937757.1	Q7Z407-2
	CSMD3	NM_052900.3		c.10013T>C	p.Phe3338Ser	missense	Exon 65 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.10520T>C	p.Phe3507Ser	missense	Exon 67 of 71	ENSP00000297405.5	Q7Z407-1
	CSMD3	ENST00000343508.7	TSL:1	c.10400T>C	p.Phe3467Ser	missense	Exon 68 of 72	ENSP00000345799.3	Q7Z407-2
	CSMD3	ENST00000455883.2	TSL:1	c.10013T>C	p.Phe3338Ser	missense	Exon 65 of 69	ENSP00000412263.2	Q7Z407-3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152094 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: 0.0000119 AC: 3 AN: 251292 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461086 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 726880

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

American (AMR) AF: 0.00 AC: 0 AN: 44714

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

East Asian (EAS) AF: 0.000177 AC: 7 AN: 39616

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111402

Other (OTH) AF: 0.00 AC: 0 AN: 60360

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152094 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74284

African (AFR) AF: 0.0000241 AC: 1 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67992

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.080
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		4.5
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Benign	0.19
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.062	B
Vest4		0.62
MutPred		0.57		Gain of disorder (P = 0.0172)
MVP		0.25
MPC		0.28
ClinPred		0.89	D
GERP RS		3.6
Varity_R		0.72
gMVP		0.81
Mutation Taster		=70/30	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: rs774419933; hg19: chr8-113249526;