7-102070339-A-G

Position:

• chr7-102070339-A-G

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.190A>G​(p.Ile64Val) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CUX1 NM_181552.4 missense, splice_region
• Scores: Splicing: ADA: 0.002262
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.83

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 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=0.2169537).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUX1	NM_181552.4	c.190A>G	p.Ile64Val	missense_variant, splice_region_variant	4/24	ENST00000292535.12
CUX1	NM_001913.5	c.223A>G	p.Ile75Val	missense_variant, splice_region_variant	4/23	ENST00000622516.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUX1	ENST00000292535.12	c.190A>G	p.Ile64Val	missense_variant, splice_region_variant	4/24	1	NM_181552.4	A2
CUX1	ENST00000622516.6	c.223A>G	p.Ile75Val	missense_variant, splice_region_variant	4/23	1	NM_001913.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 26, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.11	.;.;.;T;.;T;.;.;.;T;T;.;.;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D;D;T;.;D;D;T;D;D;.;D;D;D;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.22	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.3	.;.;.;.;.;.;.;.;.;L;L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.35	N;.;.;N;N;.;N;N;N;N;N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.27	T;.;.;T;T;.;T;T;T;T;T;T;T;T
Sift4G	Benign	0.61	T;.;.;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.76	P;.;.;P;.;P;.;D;.;D;D;.;.;.
Vest4		0.33
MutPred		0.20		.;.;.;.;.;.;.;.;.;Gain of disorder (P = 0.162);Gain of disorder (P = 0.162);Gain of disorder (P = 0.162);Gain of disorder (P = 0.162);Gain of disorder (P = 0.162);
MVP		0.13
MPC		0.46
ClinPred		0.65	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0023
dbscSNV1_RF	Benign	0.012
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-101713619;