chr1-225512688-G-T

Variant names:

• chr1-225512688-G-T
• rs75986582
• NM_018212.6:c.1391C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018212.6(ENAH):​c.1391C>A​(p.Thr464Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. T464I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ENAH NM_018212.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.98

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

Verdict is Uncertain_significance. Variant got 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.1391C>A	p.Thr464Lys	missense_variant	Exon 9 of 14	ENST00000366843.7	NP_060682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENAH	ENST00000366843.7	c.1391C>A	p.Thr464Lys	missense_variant	Exon 9 of 14	1	NM_018212.6	ENSP00000355808.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250674 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135496

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000724 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.077	T;.;.
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Uncertain	0.040	D
MutationAssessor	Benign	0.80	N;.;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.75	N;.;N
REVEL	Uncertain	0.30
Sift	Benign	0.24	T;.;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.95	P;.;D
Vest4		0.37
MutPred		0.28		Gain of methylation at T464 (P = 0.0129);.;Gain of methylation at T464 (P = 0.0129);
MVP		0.52
MPC		0.78
ClinPred		0.85	D
GERP RS		6.1
Varity_R		0.14
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.23		Position offset: 26

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs75986582; hg19: chr1-225700390;