NM_018212.6:c.1319G>C

Variant names:

• chr1-225512916-C-G
• rs139773212
• NM_018212.6:c.1319G>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_018212.6(ENAH):​c.1319G>C​(p.Gly440Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000196 in 1,613,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: ENAH NM_018212.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.96
• Publications: 5 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: Likely_benign. The variant received -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.769
• BS2: High AC in GnomAd4 at 25 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018212.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENAH	NM_018212.6	MANE Select	c.1319G>C	p.Gly440Ala	missense	Exon 8 of 14	NP_060682.2
	ENAH	NM_001420159.1		c.2060G>C	p.Gly687Ala	missense	Exon 9 of 16	NP_001407088.1
	ENAH	NM_001420160.1		c.2003G>C	p.Gly668Ala	missense	Exon 8 of 15	NP_001407089.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENAH	ENST00000366843.7	TSL:1 MANE Select	c.1319G>C	p.Gly440Ala	missense	Exon 8 of 14	ENSP00000355808.2	Q8N8S7-2
	ENAH	ENST00000366844.7	TSL:1	c.1319G>C	p.Gly440Ala	missense	Exon 8 of 15	ENSP00000355809.2	Q8N8S7-1
	ENAH	ENST00000893225.1		c.2003G>C	p.Gly668Ala	missense	Exon 8 of 15	ENSP00000563284.1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152098 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000183 AC: 46 AN: 251316 AF XY: 0.000214

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000968

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000200 AC: 292 AN: 1461808 Hom.: 0 Cov.: 31 AF XY: 0.000215 AC XY: 156 AN XY: 727206

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.000134 AC: 6 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39688

South Asian (SAS) AF: 0.000800 AC: 69 AN: 86252

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53412

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.000182 AC: 202 AN: 1111966

Other (OTH) AF: 0.0000828 AC: 5 AN: 60392

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152098 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74296

African (AFR) AF: 0.0000242 AC: 1 AN: 41392

American (AMR) AF: 0.0000655 AC: 1 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000146 Hom.: 0

Bravo AF: 0.000144

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000132 AC: 16

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	0.00078	T
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		7.0
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.93
MVP		0.89
MPC		0.97
ClinPred		0.64	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.57
Mutation Taster		=40/60	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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

dbSNP: rs139773212; hg19: chr1-225700618;