chr7-101816046-G-A

Variant names:

• chr7-101816046-G-A
• rs1164370058
• NM_001913.5:c.16G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001913.5(CUX1):​c.16G>A​(p.Gly6Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000209 in 1,433,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: CUX1 NM_001913.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 5.32
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• global developmental delay with or without impaired intellectual development

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28541607).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001913.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUX1	NM_001913.5	MANE Plus Clinical	c.16G>A	p.Gly6Arg	missense	Exon 1 of 23	NP_001904.2
	CUX1	NM_001202543.2		c.16G>A	p.Gly6Arg	missense	Exon 1 of 24	NP_001189472.1	P39880-3
	CUX1	NM_181500.4		c.16G>A	p.Gly6Arg	missense	Exon 1 of 23	NP_852477.1	Q13948-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUX1	ENST00000622516.6	TSL:1 MANE Plus Clinical	c.16G>A	p.Gly6Arg	missense	Exon 1 of 23	ENSP00000484760.2	Q13948-1
	CUX1	ENST00000360264.7	TSL:1	c.16G>A	p.Gly6Arg	missense	Exon 1 of 24	ENSP00000353401.3	P39880-3
	CUX1	ENST00000292538.9	TSL:1	c.16G>A	p.Gly6Arg	missense	Exon 1 of 23	ENSP00000292538.4	Q13948-1

Frequencies

GnomAD3 genomes AF: 0.00000675 AC: 1 AN: 148166 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

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: 0.0000150

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000156 AC: 2 AN: 1285670 Hom.: 0 Cov.: 30 AF XY: 0.00000156 AC XY: 1 AN XY: 640050

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25214

American (AMR) AF: 0.00 AC: 0 AN: 35254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.00 AC: 0 AN: 23894

South Asian (SAS) AF: 0.00 AC: 0 AN: 79906

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44478

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4876

European-Non Finnish (NFE) AF: 9.96e-7 AC: 1 AN: 1003908

Other (OTH) AF: 0.0000205 AC: 1 AN: 48756

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000983081), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000675 AC: 1 AN: 148166 Hom.: 0 Cov.: 29 AF XY: 0.0000138 AC XY: 1 AN XY: 72208

African (AFR) AF: 0.00 AC: 0 AN: 41060

American (AMR) AF: 0.00 AC: 0 AN: 14956

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3414

East Asian (EAS) AF: 0.00 AC: 0 AN: 5006

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9088

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000150 AC: 1 AN: 66544

Other (OTH) AF: 0.00 AC: 0 AN: 2054

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	CUX1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.4	L
PhyloP100		5.3
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.15
Sift	Benign	0.49	T
Sift4G	Benign	0.17	T
Polyphen		0.0040	B
Vest4		0.30
MutPred		0.38		Gain of MoRF binding (P = 0.0161)
MVP		0.068
MPC		0.67
ClinPred		0.45	T
GERP RS		1.7
PromoterAI		-0.029	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
gMVP		0.42
Mutation Taster		=70/30	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1164370058; hg19: chr7-101459326;