Genetic Variant ENAH:p.Pro334Gln (chr1-225514813-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_018212.6(ENAH):c.1001C>A(p.Pro334Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000709 in 1,409,938 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P334L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

ENAH
NM_018212.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.92

Publications

0 publications found

Variant links:

Genes affected

ENAH (HGNC:18271): (ENAH actin regulator) This gene encodes a member of the enabled/ vasodilator-stimulated phosphoprotein. Members of this gene family are involved in actin-based motility. This protein is involved in regulating the assembly of actin filaments and modulates cell adhesion and motility. Alternate splice variants of this gene have been correlated with tumor invasiveness in certain tissues and these variants may serve as prognostic markers. A pseudogene of this gene is found on chromosome 3. [provided by RefSeq, Sep 2016]

ENAH links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENAH	NM_018212.6 link	c.1001C>A	p.Pro334Gln	missense_variant	Exon 7 of 14	ENST00000366843.7	NP_060682.2	Q8N8S7-2A0A4D6J698

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENAH	ENST00000366843.7 link	c.1001C>A	p.Pro334Gln	missense_variant	Exon 7 of 14	1	NM_018212.6	ENSP00000355808.2		Q8N8S7-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.09e-7

AC:

AN:

1409938

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

700404

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

30864

American (AMR)

AF:

0.00

AC:

AN:

32840

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24314

East Asian (EAS)

AF:

0.00

AC:

AN:

37830

South Asian (SAS)

AF:

0.00

AC:

AN:

78816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51940

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4598

European-Non Finnish (NFE)

AF:

9.17e-7

AC:

AN:

1090528

Other (OTH)

AF:

0.00

AC:

AN:

58208

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.074

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.48

T;.;.

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.80

T;T;T

M_CAP

Uncertain

0.23

MetaRNN

Uncertain

0.53

D;D;D

MetaSVM

Uncertain

0.44

MutationAssessor

Uncertain

2.8

M;.;M

PhyloP100

4.9

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-2.9

D;.;D

REVEL

Uncertain

0.40

Sift

Benign

0.056

T;.;T

Sift4G

Uncertain

0.046

D;T;D

Polyphen

1.0

D;.;D

Vest4

0.53

MutPred

0.26

Loss of glycosylation at P334 (P = 0.0012);.;Loss of glycosylation at P334 (P = 0.0012);

MVP

0.71

MPC

0.90

ClinPred

0.98

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.10

gMVP

0.18

Mutation Taster

=62/38

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over