NM_198123.2:c.10740+7A>G

Variant names:

• chr8-112234358-T-C
• rs368478953
• NM_198123.2:c.10740+7A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_198123.2(CSMD3):​c.10740+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000449 in 1,547,270 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (4 hom.)
• Consequence: CSMD3 NM_198123.2 splice_region, intron
• Scores: Splicing: ADA: 0.00007022
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.199
• 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 8-112234358-T-C is Benign according to our data. Variant chr8-112234358-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2658756.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 66 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.10740+7A>G		splice_region intron	N/A	NP_937756.1	Q7Z407-1
	CSMD3	NM_198124.2		c.10620+7A>G		splice_region intron	N/A	NP_937757.1	Q7Z407-2
	CSMD3	NM_052900.3		c.10233+7A>G		splice_region intron	N/A	NP_443132.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSMD3	ENST00000297405.10	TSL:1 MANE Select	c.10740+7A>G		splice_region intron	N/A	ENSP00000297405.5	Q7Z407-1
	CSMD3	ENST00000343508.7	TSL:1	c.10620+7A>G		splice_region intron	N/A	ENSP00000345799.3	Q7Z407-2
	CSMD3	ENST00000455883.2	TSL:1	c.10233+7A>G		splice_region intron	N/A	ENSP00000412263.2	Q7Z407-3

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.0132

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000794 AC: 199 AN: 250628 AF XY: 0.000708

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.0152

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000946

Gnomad NFE exome AF: 0.000247

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000451 AC: 629 AN: 1395096 Hom.: 4 Cov.: 24 AF XY: 0.000464 AC XY: 324 AN XY: 698316

African (AFR) AF: 0.0000621 AC: 2 AN: 32204

American (AMR) AF: 0.000202 AC: 9 AN: 44622

Ashkenazi Jewish (ASJ) AF: 0.0139 AC: 358 AN: 25692

East Asian (EAS) AF: 0.00 AC: 0 AN: 39258

South Asian (SAS) AF: 0.00 AC: 0 AN: 84882

European-Finnish (FIN) AF: 0.0000950 AC: 5 AN: 52652

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5652

European-Non Finnish (NFE) AF: 0.000188 AC: 198 AN: 1051958

Other (OTH) AF: 0.000980 AC: 57 AN: 58176

GnomAD4 genome AF: 0.000434 AC: 66 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.000444 AC XY: 33 AN XY: 74336

African (AFR) AF: 0.0000483 AC: 2 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0132 AC: 46 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00185 Hom.: 1

Bravo AF: 0.000495

EpiCase AF: 0.000274

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.2
DANN	Benign	0.52
PhyloP100		0.20
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000070
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.080		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: rs368478953; hg19: chr8-113246587;