NM_001913.5:c.38A>G

Variant names:

• chr7-101816068-A-G
• rs1219523928
• NM_001913.5:c.38A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001913.5(CUX1):​c.38A>G​(p.Lys13Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000106 in 1,417,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: CUX1 NM_001913.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.90
• 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.34179485).
• BS2: High AC in GnomAdExome4 at 13 AD gene.

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.38A>G	p.Lys13Arg	missense	Exon 1 of 23	NP_001904.2
	CUX1	NM_001202543.2		c.38A>G	p.Lys13Arg	missense	Exon 1 of 24	NP_001189472.1	P39880-3
	CUX1	NM_181500.4		c.38A>G	p.Lys13Arg	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.38A>G	p.Lys13Arg	missense	Exon 1 of 23	ENSP00000484760.2	Q13948-1
	CUX1	ENST00000360264.7	TSL:1	c.38A>G	p.Lys13Arg	missense	Exon 1 of 24	ENSP00000353401.3	P39880-3
	CUX1	ENST00000292538.9	TSL:1	c.38A>G	p.Lys13Arg	missense	Exon 1 of 23	ENSP00000292538.4	Q13948-1

Frequencies

GnomAD3 genomes AF: 0.0000136 AC: 2 AN: 146846 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: 0.0000302

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000473 AC: 1 AN: 211320 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000103

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000102 AC: 13 AN: 1270160 Hom.: 0 Cov.: 30 AF XY: 0.00000791 AC XY: 5 AN XY: 632356

African (AFR) AF: 0.00 AC: 0 AN: 24786

American (AMR) AF: 0.00 AC: 0 AN: 34658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18860

East Asian (EAS) AF: 0.00 AC: 0 AN: 22364

South Asian (SAS) AF: 0.00 AC: 0 AN: 79452

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43292

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4776

European-Non Finnish (NFE) AF: 0.0000131 AC: 13 AN: 994360

Other (OTH) AF: 0.00 AC: 0 AN: 47612

GnomAD4 genome AF: 0.0000136 AC: 2 AN: 146846 Hom.: 0 Cov.: 29 AF XY: 0.0000140 AC XY: 1 AN XY: 71514

African (AFR) AF: 0.00 AC: 0 AN: 40630

American (AMR) AF: 0.00 AC: 0 AN: 14880

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3400

East Asian (EAS) AF: 0.00 AC: 0 AN: 4828

South Asian (SAS) AF: 0.00 AC: 0 AN: 4760

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8856

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.0000302 AC: 2 AN: 66242

Other (OTH) AF: 0.00 AC: 0 AN: 2036

Alfa AF: 0.0000301 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.91	L
PhyloP100		2.9
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.17
Sift	Benign	0.28	T
Sift4G	Benign	0.32	T
Polyphen		0.27	B
Vest4		0.22
MutPred		0.33		Loss of methylation at K13 (P = 0.0098)
MVP		0.15
MPC		0.45
ClinPred		0.81	D
GERP RS		1.3
PromoterAI		-0.064	Neutral
gMVP		0.34
Mutation Taster		=83/17	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1219523928; hg19: chr7-101459348;