chr7-27245944-C-A

Variant names:

• chr7-27245944-C-A
• rs763601537
• NM_001989.5:c.743C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_001989.5(EVX1):​c.743C>A​(p.Pro248Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000166 in 1,448,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: EVX1 NM_001989.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.41

Genes affected

EVX1 (HGNC:3506): (even-skipped homeobox 1) This gene encodes a member of the even-skipped homeobox family characterized by the presence of a homeodomain closely related to the Drosophila even-skipped (eve) segmentation gene of the pair-rule class. The encoded protein may play an important role as a transcriptional repressor during embryogenesis. [provided by RefSeq, Jul 2008]

EVX1-AS (HGNC:40223): (EVX1 antisense RNA) Predicted to enable chromatin binding activity. Predicted to be part of histone methyltransferase complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.913
• BS2: High AC in GnomAdExome4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EVX1	NM_001989.5	c.743C>A	p.Pro248Gln	missense_variant	Exon 3 of 3	ENST00000496902.7	NP_001980.1
EVX1	NM_001304519.2	c.197C>A	p.Pro66Gln	missense_variant	Exon 3 of 3		NP_001291448.1
EVX1	NM_001304520.2	c.197C>A	p.Pro66Gln	missense_variant	Exon 4 of 4		NP_001291449.1
EVX1-AS	NR_120507.1	n.269+1017G>T		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EVX1	ENST00000496902.7	c.743C>A	p.Pro248Gln	missense_variant	Exon 3 of 3	1	NM_001989.5	ENSP00000419266.3
EVX1	ENST00000222761.7	c.*82C>A		3_prime_UTR_variant	Exon 3 of 3	1		ENSP00000222761.3
EVX1	ENST00000580535.1	c.*82C>A		3_prime_UTR_variant	Exon 4 of 4	2		ENSP00000463759.1
EVX1-AS	ENST00000517726.1	n.269+1017G>T		intron_variant	Intron 1 of 3	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000166 AC: 24 AN: 1448950 Hom.: 0 Cov.: 31 AF XY: 0.00000971 AC XY: 7 AN XY: 720850

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000259

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000208

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 09, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.743C>A (p.P248Q) alteration is located in exon 3 (coding exon 3) of the EVX1 gene. This alteration results from a C to A substitution at nucleotide position 743, causing the proline (P) at amino acid position 248 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.3	M
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-7.2	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.37		Gain of MoRF binding (P = 0.0512);
MVP		0.99
MPC		1.5
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.70
gMVP		0.83

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: rs763601537; hg19: chr7-27285563;