Genetic Variant NM_018212.6:c.1046C>T (chr1-225514768-G-A) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_018212.6(ENAH):c.1046C>T(p.Pro349Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000028 ( 0 hom., cov: 19)

Exomes 𝑓: 0.000052 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ENAH
NM_018212.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.24

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.36536258).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENAH	NM_018212.6 link	c.1046C>T	p.Pro349Leu	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.1046C>T	p.Pro349Leu	missense_variant	Exon 7 of 14	1	NM_018212.6	ENSP00000355808.2		Q8N8S7-2

Frequencies

GnomAD3 genomes

AF:

0.0000278

AC:

AN:

143976

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000520

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:

0.0000152

Gnomad OTH

AF:

0.000518

GnomAD2 exomes

AF:

0.0000229

AC:

AN:

174832

AF XY:

0.0000416

show subpopulations

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:

0.0000533

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000521

AC:

AN:

1325500

Hom.:

Cov.:

AF XY:

0.0000591

AC XY:

AN XY:

660416

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28238

American (AMR)

AF:

0.0000325

AC:

AN:

30790

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23638

East Asian (EAS)

AF:

0.00

AC:

AN:

33538

South Asian (SAS)

AF:

0.00

AC:

AN:

76912

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50246

Middle Eastern (MID)

AF:

0.000257

AC:

AN:

3890

European-Non Finnish (NFE)

AF:

0.0000635

AC:

AN:

1023040

Other (OTH)

AF:

0.0000362

AC:

AN:

55208

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000278

AC:

AN:

143976

Hom.:

Cov.:

AF XY:

0.0000286

AC XY:

AN XY:

69942

show subpopulations

African (AFR)

AF:

0.0000520

AC:

AN:

38428

American (AMR)

AF:

0.00

AC:

AN:

14342

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3382

East Asian (EAS)

AF:

0.00

AC:

AN:

4904

South Asian (SAS)

AF:

0.00

AC:

AN:

4272

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9942

Middle Eastern (MID)

AF:

0.00

AC:

AN:

304

European-Non Finnish (NFE)

AF:

0.0000152

AC:

AN:

65584

Other (OTH)

AF:

0.000518

AC:

AN:

1930

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000336

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 16, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1046C>T (p.P349L) alteration is located in exon 7 (coding exon 7) of the ENAH gene. This alteration results from a C to T substitution at nucleotide position 1046, causing the proline (P) at amino acid position 349 to be replaced by a leucine (L). 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

Benign

0.11

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

D;.;.

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.76

T;D;T

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.37

T;T;T

MetaSVM

Uncertain

0.56

MutationAssessor

Uncertain

2.2

M;.;M

PhyloP100

3.2

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-5.2

D;.;D

REVEL

Benign

0.28

Sift

Uncertain

0.013

D;.;D

Sift4G

Uncertain

0.023

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.36

MVP

0.57

MPC

0.94

ClinPred

0.91

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.29

gMVP

0.19

Mutation Taster

=88/12

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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NM_018212.6:c.1046C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over