NM_001913.5:c.63+3C>G

Variant names:

• chr7-101816096-C-G
• rs761227961
• NM_001913.5:c.63+3C>G

Variant summary

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

The NM_001913.5(CUX1):​c.63+3C>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 0.000000817 in 1,224,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 8.2e-7 (0 hom.)
• Consequence: CUX1 NM_001913.5 splice_region, intron
• Scores: Splicing: ADA: 0.004903
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.499
• Publications: 0 publications found

Genes affected

CUX1 (HGNC:2557): (cut like homeobox 1) The protein encoded by this gene is a member of the homeodomain family of DNA binding proteins. It may regulate gene expression, morphogenesis, and differentiation and it may also play a role in the cell cycle progession. Several alternatively spliced transcript variants encoding different isoforms have been identified.[provided by RefSeq, Feb 2011]

CUX1 Gene-Disease associations (from GenCC):

• global developmental delay with or without impaired intellectual development

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

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 (BayesDel_noAF=-0.26).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001913.5. 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
	CUX1	NM_001913.5	MANE Plus Clinical	c.63+3C>G		splice_region intron	N/A	NP_001904.2
	CUX1	NM_001202543.2		c.63+3C>G		splice_region intron	N/A	NP_001189472.1	P39880-3
	CUX1	NM_181500.4		c.63+3C>G		splice_region intron	N/A	NP_852477.1	Q13948-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUX1	ENST00000622516.6	TSL:1 MANE Plus Clinical	c.63+3C>G		splice_region intron	N/A	ENSP00000484760.2	Q13948-1
	CUX1	ENST00000360264.7	TSL:1	c.63+3C>G		splice_region intron	N/A	ENSP00000353401.3	P39880-3
	CUX1	ENST00000292538.9	TSL:1	c.63+3C>G		splice_region intron	N/A	ENSP00000292538.4	Q13948-1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 8.17e-7 AC: 1 AN: 1224232 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 609482

African (AFR) AF: 0.00 AC: 0 AN: 23726

American (AMR) AF: 0.00 AC: 0 AN: 32248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17390

East Asian (EAS) AF: 0.00 AC: 0 AN: 18840

South Asian (SAS) AF: 0.00 AC: 0 AN: 76112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39770

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4540

European-Non Finnish (NFE) AF: 0.00000103 AC: 1 AN: 966932

Other (OTH) AF: 0.00 AC: 0 AN: 44674

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Benign	0.94
PhyloP100		0.50
PromoterAI		-0.094	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0049
dbscSNV1_RF	Benign	0.13

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

Other links and lift over

dbSNP: rs761227961; hg19: chr7-101459376;