7-101916181-C-T

Position:

chr7-101916181-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4BS1_SupportingBS2

The NM_181552.4(CUX1):c.97C>T(p.Arg33Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

CUX1
NM_181552.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.23

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 Likely_benign. Variant got -5 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=0.31950623).

BS1

Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.00000684 (10/1461652) while in subpopulation AFR AF= 0.000149 (5/33476). AF 95% confidence interval is 0.0000585. There are 0 homozygotes in gnomad4_exome. There are 4 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUX1	NM_181552.4 linkuse as main transcript	c.97C>T	p.Arg33Trp	missense_variant	2/24	ENST00000292535.12
CUX1	NM_001913.5 linkuse as main transcript	c.130C>T	p.Arg44Trp	missense_variant	2/23	ENST00000622516.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUX1	ENST00000292535.12 linkuse as main transcript	c.97C>T	p.Arg33Trp	missense_variant	2/24	1	NM_181552.4	A2	P39880-1
CUX1	ENST00000622516.6 linkuse as main transcript	c.130C>T	p.Arg44Trp	missense_variant	2/23	1	NM_001913.5		Q13948-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251484

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461652

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727128

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 29, 2022

Variant summary: CUX1 c.130C>T (p.Arg44Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251484 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.130C>T in individuals affected with Global Developmental Delay With Or Without Impaired Intellectual Development and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.31

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.36

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

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.98

D;D;D;.;D;D;D;D;.;D;D;D;D

M_CAP

Benign

0.020

MetaRNN

Benign

0.32

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

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.6

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

MutationTaster

Benign

0.99

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

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-3.6

D;.;.;D;.;D;D;D;D;D;D;D;D

REVEL

Benign

0.23

Sift

Uncertain

0.0010

D;.;.;D;.;D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.0040

D;.;.;D;D;D;D;D;D;D;D;D;D

Polyphen

1.0

D;.;.;D;D;.;D;.;D;D;.;.;.

Vest4

0.46

MutPred

0.30

.;.;.;.;.;.;.;.;Gain of methylation at K32 (P = 0.0367);Gain of methylation at K32 (P = 0.0367);Gain of methylation at K32 (P = 0.0367);Gain of methylation at K32 (P = 0.0367);Gain of methylation at K32 (P = 0.0367);

MVP

0.10

MPC

0.58

ClinPred

0.95

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.21

gMVP

0.77

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