7-27243235-C-A

Variant names:

• chr7-27243235-C-A
• rs1033939449
• NM_001989.5:c.205C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001989.5(EVX1):​c.205C>A​(p.Pro69Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P69S) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: EVX1 NM_001989.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.255
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14703923).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001989.5. 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
	EVX1	NM_001989.5	MANE Select	c.205C>A	p.Pro69Thr	missense	Exon 1 of 3	NP_001980.1	P49640-1
	EVX1	NM_001304519.2		c.-287C>A		5_prime_UTR	Exon 1 of 3	NP_001291448.1	P49640-2
	EVX1	NM_001304520.2		c.-339C>A		5_prime_UTR	Exon 1 of 4	NP_001291449.1	P49640-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVX1	ENST00000496902.7	TSL:1 MANE Select	c.205C>A	p.Pro69Thr	missense	Exon 1 of 3	ENSP00000419266.3	P49640-1
	EVX1	ENST00000222761.7	TSL:1	c.205C>A	p.Pro69Thr	missense	Exon 1 of 3	ENSP00000222761.3	F8W9J5
	EVX1-AS	ENST00000517726.1	TSL:3	n.270-1225G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152176 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74322

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

African (AFR) AF: 0.0000241 AC: 1 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	10
DANN	Benign	0.91
DEOGEN2	Benign	0.054	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.51
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.64	T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.26
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.14
Sift	Benign	0.061	T
Sift4G	Benign	0.19	T
Polyphen		0.43	B
Vest4		0.092
MutPred		0.23		Gain of phosphorylation at P69 (P = 0.0058)
MVP		0.96
MPC		0.69
ClinPred		0.098	T
GERP RS		-0.20
PromoterAI		-0.17	Neutral
Varity_R		0.13
gMVP		0.23
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs1033939449; hg19: chr7-27282854;