chr7-102070411-G-A

Position:

chr7-102070411-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_181552.4(CUX1):c.262G>A(p.Val88Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00365 in 1,608,414 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0038 ( 19 hom. )

Consequence

CUX1
NM_181552.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 9.23

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CUX1. . Gene score misZ 3.7492 (greater than the threshold 3.09). Trascript score misZ 3.103 (greater than threshold 3.09). GenCC has associacion of gene with global developmental delay with or without impaired intellectual development, autosomal dominant non-syndromic intellectual disability.

BP4

Computational evidence support a benign effect (MetaRNN=0.011179209).

BP6

Variant 7-102070411-G-A is Benign according to our data. Variant chr7-102070411-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 709065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00212 (323/152238) while in subpopulation NFE AF= 0.0037 (252/68024). AF 95% confidence interval is 0.00333. There are 1 homozygotes in gnomad4. There are 130 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 323 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUX1	NM_181552.4 linkuse as main transcript	c.262G>A	p.Val88Ile	missense_variant	4/24	ENST00000292535.12
CUX1	NM_001913.5 linkuse as main transcript	c.295G>A	p.Val99Ile	missense_variant	4/23	ENST00000622516.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUX1	ENST00000292535.12 linkuse as main transcript	c.262G>A	p.Val88Ile	missense_variant	4/24	1	NM_181552.4	A2	P39880-1
CUX1	ENST00000622516.6 linkuse as main transcript	c.295G>A	p.Val99Ile	missense_variant	4/23	1	NM_001913.5		Q13948-1

Frequencies

GnomAD3 genomes

AF:

0.00211

AC:

321

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00370

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00203

AC:

494

AN:

243800

Hom.:

AF XY:

0.00218

AC XY:

288

AN XY:

132174

show subpopulations

Gnomad AFR exome

AF:

0.000704

Gnomad AMR exome

AF:

0.00114

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00162

Gnomad FIN exome

AF:

0.000421

Gnomad NFE exome

AF:

0.00338

Gnomad OTH exome

AF:

0.00236

GnomAD4 exome

AF:

0.00381

AC:

5554

AN:

1456176

Hom.:

Cov.:

AF XY:

0.00377

AC XY:

2731

AN XY:

724384

show subpopulations

Gnomad4 AFR exome

AF:

0.000516

Gnomad4 AMR exome

AF:

0.00124

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00172

Gnomad4 FIN exome

AF:

0.000301

Gnomad4 NFE exome

AF:

0.00460

Gnomad4 OTH exome

AF:

0.00342

GnomAD4 genome

AF:

0.00212

AC:

323

AN:

152238

Hom.:

Cov.:

AF XY:

0.00175

AC XY:

130

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.000722

Gnomad4 AMR

AF:

0.00157

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00290

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.00370

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00204

Hom.:

Bravo

AF:

0.00206

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00500

AC:

ExAC

AF:

0.00206

AC:

250

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	CUX1: BS1, BS2 -

CUX1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 10, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.28

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

.;.;.;T;.;T;.;.;.;T;T;.;.;.

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.81

T;D;D;.;D;D;D;D;D;.;D;D;D;D

M_CAP

Benign

0.017

MetaRNN

Benign

0.011

T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.4

.;.;.;.;.;.;.;.;.;L;L;L;L;L

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.42

N;.;.;N;N;.;N;N;N;N;N;N;N;N

REVEL

Benign

0.13

Sift

Benign

0.28

T;.;.;T;T;.;T;D;T;D;D;D;D;D

Sift4G

Benign

0.43

T;.;.;T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.67

P;.;.;P;.;P;.;D;.;D;D;.;.;.

Vest4

0.40

MVP

0.24

MPC

0.45

ClinPred

0.042

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.091

gMVP

0.65

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over