7-102104408-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.479T>C(p.Ile160Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,200 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: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CUX1 NM_181552.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.73

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=0.20903313).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUX1	NM_181552.4	c.479T>C	p.Ile160Thr	missense_variant	6/24	ENST00000292535.12
CUX1	NM_001913.5	c.512T>C	p.Ile171Thr	missense_variant	6/23	ENST00000622516.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUX1	ENST00000292535.12	c.479T>C	p.Ile160Thr	missense_variant	6/24	1	NM_181552.4	A2
CUX1	ENST00000622516.6	c.512T>C	p.Ile171Thr	missense_variant	6/23	1	NM_001913.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250696 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135542

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460200 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726482

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.000111 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 28, 2023

The c.512T>C (p.I171T) alteration is located in exon 6 (coding exon 6) of the CUX1 gene. This alteration results from a T to C substitution at nucleotide position 512, causing the isoleucine (I) at amino acid position 171 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 17, 2023

This variant has not been reported in the literature in individuals affected with CUX1-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CUX1 protein function. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 171 of the CUX1 protein (p.Ile171Thr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Benign	0.070
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D;.;D;D;D;D;D;.;D;D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.21	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.4	N;.;.;N;N;.;N;N;N;N;N;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.080	T;.;.;T;T;.;T;T;D;T;T;T;T;T
Sift4G	Benign	0.45	T;.;.;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.23	B;.;.;B;.;B;.;P;.;P;P;.;.;.
Vest4		0.39
MutPred		0.16		.;.;.;.;.;.;.;.;.;Loss of methylation at K164 (P = 0.0845);Loss of methylation at K164 (P = 0.0845);Loss of methylation at K164 (P = 0.0845);Loss of methylation at K164 (P = 0.0845);Loss of methylation at K164 (P = 0.0845);
MVP		0.17
MPC		0.70
ClinPred		0.39	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.64

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: rs1554487735; hg19: chr7-101747688;