1-225514696-G-A

Variant names:

• chr1-225514696-G-A
• NM_018212.6:c.1118C>T

Variant summary

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

The NM_018212.6(ENAH):​c.1118C>T​(p.Pro373Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 29)
• Consequence: ENAH NM_018212.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.46
• Publications: 0 publications found

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]

ACMG classification

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	c.1118C>T	p.Pro373Leu	missense_variant	Exon 7 of 14	ENST00000366843.7	NP_060682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENAH	ENST00000366843.7	c.1118C>T	p.Pro373Leu	missense_variant	Exon 7 of 14	1	NM_018212.6	ENSP00000355808.2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1118C>T (p.P373L) 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 1118, causing the proline (P) at amino acid position 373 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	Uncertain	0.43
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;.;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.63	D;D;D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Pathogenic	3.3	M;.;M
PhyloP100		8.5
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.0	D;.;D
REVEL	Benign	0.27
Sift	Benign	0.96	T;.;T
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;.;B
Vest4		0.75
MutPred		0.17		Loss of relative solvent accessibility (P = 0.0071);.;Loss of relative solvent accessibility (P = 0.0071);
MVP		0.62
MPC		0.95
ClinPred		1.0	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.17
gMVP		0.19
Mutation Taster		=71/29	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

hg19: chr1-225702398;