NM_181552.4:c.724-3875A>G

Variant names:

• chr7-102166571-A-G
• rs365836
• NM_181552.4:c.724-3875A>G

Variant summary

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

The NM_181552.4(CUX1):​c.724-3875A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.314 in 152,024 control chromosomes in the GnomAD database, including 8,431 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.31 (8431 hom., cov: 31)
• Consequence: CUX1 NM_181552.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.69
• Publications: 21 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.466 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUX1	NM_181552.4	c.724-3875A>G		intron_variant	Intron 9 of 23	ENST00000292535.12	NP_853530.2
CUX1	NM_001913.5	c.757-3875A>G		intron_variant	Intron 9 of 22	ENST00000622516.6	NP_001904.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUX1	ENST00000292535.12	c.724-3875A>G		intron_variant	Intron 9 of 23	1	NM_181552.4	ENSP00000292535.7
CUX1	ENST00000622516.6	c.757-3875A>G		intron_variant	Intron 9 of 22	1	NM_001913.5	ENSP00000484760.2

Frequencies

GnomAD3 genomes AF: 0.314 AC: 47730 AN: 151906 Hom.: 8414 Cov.: 31

Gnomad AFR AF: 0.471

Gnomad AMI AF: 0.381

Gnomad AMR AF: 0.289

Gnomad ASJ AF: 0.342

Gnomad EAS AF: 0.0828

Gnomad SAS AF: 0.232

Gnomad FIN AF: 0.215

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.261

Gnomad OTH AF: 0.310

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.314 AC: 47799 AN: 152024 Hom.: 8431 Cov.: 31 AF XY: 0.309 AC XY: 22932 AN XY: 74308

African (AFR) AF: 0.472 AC: 19536 AN: 41424

American (AMR) AF: 0.289 AC: 4417 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.342 AC: 1186 AN: 3472

East Asian (EAS) AF: 0.0832 AC: 430 AN: 5168

South Asian (SAS) AF: 0.230 AC: 1110 AN: 4816

European-Finnish (FIN) AF: 0.215 AC: 2282 AN: 10592

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.261 AC: 17744 AN: 67960

Other (OTH) AF: 0.309 AC: 650 AN: 2106

Alfa AF: 0.273 Hom.: 20937

Bravo AF: 0.326

Asia WGS AF: 0.192 AC: 673 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.0030
DANN	Benign	0.25
PhyloP100		-2.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs365836; hg19: chr7-101809851;