chr7-101916233-G-A

Variant names:

• chr7-101916233-G-A
• rs56091128
• NM_181552.4:c.141+8G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_181552.4(CUX1):​c.141+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0646 in 1,563,538 control chromosomes in the GnomAD database, including 3,863 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 Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.047 (226 hom., cov: 32)
  • Exomes 𝑓: 0.067 (3637 hom.)
• Consequence: CUX1 NM_181552.4 splice_region, intron
• Scores: Splicing: ADA: 0.0003162
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.47
• Publications: 5 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 7-101916233-G-A is Benign according to our data. Variant chr7-101916233-G-A is described in ClinVar as Benign. ClinVar VariationId is 3060457.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0702 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181552.4. 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_181552.4	MANE Select	c.141+8G>A		splice_region intron	N/A	NP_853530.2	P39880-1
	CUX1	NM_001913.5	MANE Plus Clinical	c.174+8G>A		splice_region intron	N/A	NP_001904.2
	CUX1	NM_001202543.2		c.174+8G>A		splice_region intron	N/A	NP_001189472.1	P39880-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUX1	ENST00000292535.12	TSL:1 MANE Select	c.141+8G>A		splice_region intron	N/A	ENSP00000292535.7	P39880-1
	CUX1	ENST00000622516.6	TSL:1 MANE Plus Clinical	c.174+8G>A		splice_region intron	N/A	ENSP00000484760.2	Q13948-1
	CUX1	ENST00000360264.7	TSL:1	c.174+8G>A		splice_region intron	N/A	ENSP00000353401.3	P39880-3

Frequencies

GnomAD3 genomes AF: 0.0465 AC: 7075 AN: 152044 Hom.: 225 Cov.: 32

Gnomad AFR AF: 0.0126

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0333

Gnomad ASJ AF: 0.0582

Gnomad EAS AF: 0.000967

Gnomad SAS AF: 0.0447

Gnomad FIN AF: 0.0604

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0719

Gnomad OTH AF: 0.0422

GnomAD2 exomes AF: 0.0528 AC: 13276 AN: 251380 AF XY: 0.0532

Gnomad AFR exome AF: 0.0121

Gnomad AMR exome AF: 0.0459

Gnomad ASJ exome AF: 0.0557

Gnomad EAS exome AF: 0.000435

Gnomad FIN exome AF: 0.0618

Gnomad NFE exome AF: 0.0686

Gnomad OTH exome AF: 0.0491

GnomAD4 exome AF: 0.0666 AC: 93972 AN: 1411376 Hom.: 3637 Cov.: 23 AF XY: 0.0657 AC XY: 46350 AN XY: 705168

African (AFR) AF: 0.0107 AC: 348 AN: 32498

American (AMR) AF: 0.0449 AC: 2004 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.0575 AC: 1485 AN: 25818

East Asian (EAS) AF: 0.000482 AC: 19 AN: 39440

South Asian (SAS) AF: 0.0498 AC: 4236 AN: 85138

European-Finnish (FIN) AF: 0.0619 AC: 3296 AN: 53288

Middle Eastern (MID) AF: 0.0222 AC: 126 AN: 5664

European-Non Finnish (NFE) AF: 0.0742 AC: 79125 AN: 1066140

Other (OTH) AF: 0.0567 AC: 3333 AN: 58758

GnomAD4 genome AF: 0.0465 AC: 7078 AN: 152162 Hom.: 226 Cov.: 32 AF XY: 0.0436 AC XY: 3243 AN XY: 74370

African (AFR) AF: 0.0125 AC: 520 AN: 41536

American (AMR) AF: 0.0332 AC: 507 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0582 AC: 202 AN: 3470

East Asian (EAS) AF: 0.000969 AC: 5 AN: 5160

South Asian (SAS) AF: 0.0452 AC: 217 AN: 4806

European-Finnish (FIN) AF: 0.0604 AC: 640 AN: 10592

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0719 AC: 4891 AN: 67996

Other (OTH) AF: 0.0418 AC: 88 AN: 2106

Alfa AF: 0.0566 Hom.: 289

Bravo AF: 0.0426

Asia WGS AF: 0.0180 AC: 62 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	CUX1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.2
DANN	Benign	0.44
PhyloP100		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00032
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.040		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: rs56091128; hg19: chr7-101559513;