Genetic Variant ENAH:p.Ser295Phe (chr1-225517225-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_018212.6(ENAH):c.884C>T(p.Ser295Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000388 in 1,547,346 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

ENAH
NM_018212.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.71

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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.20730466).

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENAH	NM_018212.6 link	c.884C>T	p.Ser295Phe	missense_variant	Exon 6 of 14	ENST00000366843.7	NP_060682.2	Q8N8S7-2A0A4D6J698

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ENAH	ENST00000366843.7 link	c.884C>T	p.Ser295Phe	missense_variant	Exon 6 of 14	1	NM_018212.6	ENSP00000355808.2	Q8N8S7-2
ENAH	ENST00000366844.7 link	c.884C>T	p.Ser295Phe	missense_variant	Exon 6 of 15	1		ENSP00000355809.2	Q8N8S7-1
ENAH	ENST00000635051.1 link	c.1580C>T	p.Ser527Phe	missense_variant	Exon 7 of 15	5		ENSP00000489607.1	A0A0U1RRM6
ENAH	ENST00000696609.1 link	c.1202C>T	p.Ser401Phe	missense_variant	Exon 3 of 12			ENSP00000512753.1	A0A8Q3WLE0

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

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

GnomAD2 exomes

AF:

0.0000259

AC:

AN:

154464

AF XY:

0.0000372

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000350

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000358

AC:

AN:

1395148

Hom.:

Cov.:

AF XY:

0.00000291

AC XY:

AN XY:

687642

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31566

American (AMR)

AF:

0.00

AC:

AN:

35524

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24812

East Asian (EAS)

AF:

0.000112

AC:

AN:

35762

South Asian (SAS)

AF:

0.00

AC:

AN:

78684

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49080

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4898

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1077042

Other (OTH)

AF:

0.0000173

AC:

AN:

57780

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.000193

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 25, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.884C>T (p.S295F) alteration is located in exon 6 (coding exon 6) of the ENAH gene. This alteration results from a C to T substitution at nucleotide position 884, causing the serine (S) at amino acid position 295 to be replaced by a phenylalanine (F). 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

0.20

BayesDel_addAF

Benign

-0.032

BayesDel_noAF

Uncertain

0.030

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;.;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.79

T;D;D

M_CAP

Uncertain

0.095

MetaRNN

Benign

0.21

T;T;T

MetaSVM

Uncertain

0.69

MutationAssessor

Benign

1.7

L;.;L

PhyloP100

5.7

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.6

N;.;N

REVEL

Uncertain

0.44

Sift

Pathogenic

0.0

D;.;D

Sift4G

Benign

0.39

T;T;T

Polyphen

1.0

D;.;D

Vest4

0.19

MutPred

0.17

Loss of phosphorylation at S295 (P = 0.0256);.;Loss of phosphorylation at S295 (P = 0.0256);

MVP

0.74

MPC

0.31

ClinPred

0.33

GERP RS

5.3

Varity_R

0.29

gMVP

0.30

Mutation Taster

=54/46

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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1-225517225-G-A

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