7-102097370-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_181552.4(CUX1):c.275T>C(p.Val92Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,455,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CUX1 NM_181552.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.49

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CUX1
• BP4: Computational evidence support a benign effect (MetaRNN=0.17059499).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUX1	NM_181552.4	c.275T>C	p.Val92Ala	missense_variant	5/24	ENST00000292535.12
CUX1	NM_001913.5	c.308T>C	p.Val103Ala	missense_variant	5/23	ENST00000622516.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUX1	ENST00000292535.12	c.275T>C	p.Val92Ala	missense_variant	5/24	1	NM_181552.4	A2
CUX1	ENST00000622516.6	c.308T>C	p.Val103Ala	missense_variant	5/23	1	NM_001913.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000409 AC: 1 AN: 244626 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 132308

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000347

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455716 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 724206

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Global developmental delay with or without impaired intellectual development Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 06, 2020

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	21
Dann	Uncertain	0.99
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.011
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.76	T;T;T;.;T;T;T;T;.;T;T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.0	N;.;.;N;N;.;N;N;N;N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.040	D;.;.;D;D;.;D;T;T;T;T;T;T
Sift4G	Benign	0.50	T;.;.;T;T;T;T;T;T;T;T;T;T
Polyphen		0.17	B;.;.;B;.;B;.;P;B;B;.;.;.
Vest4		0.54
MutPred		0.28		.;.;.;.;.;.;.;.;Gain of disorder (P = 0.0796);Gain of disorder (P = 0.0796);Gain of disorder (P = 0.0796);Gain of disorder (P = 0.0796);Gain of disorder (P = 0.0796);
MVP		0.11
MPC		0.67
ClinPred		0.32	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.037
gMVP		0.78

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

Other links and lift over

dbSNP: rs782042708; hg19: chr7-101740650;