rs144778786

Variant names:

• chr17-31318487-T-C
• rs144778786
• NM_014210.4:c.527A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_014210.4(EVI2A):​c.527A>G​(p.Gln176Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00477 in 1,614,056 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (20 hom.)
• Consequence: EVI2A NM_014210.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.42
• Publications: 11 publications found

Genes affected

EVI2A (HGNC:3499): (ecotropic viral integration site 2A) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000265118 (HGNC:):

NF1 (HGNC:7765): (neurofibromin 1) This gene product appears to function as a negative regulator of the ras signal transduction pathway. Mutations in this gene have been linked to neurofibromatosis type 1, juvenile myelomonocytic leukemia and Watson syndrome. The mRNA for this gene is subject to RNA editing (CGA>UGA->Arg1306Term) resulting in premature translation termination. Alternatively spliced transcript variants encoding different isoforms have also been described for this gene. [provided by RefSeq, Jul 2008]

NF1 Gene-Disease associations (from GenCC):

• neurofibromatosis type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
• neurofibromatosis-Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia
• Moyamoya disease

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010436207).
• BP6: Variant 17-31318487-T-C is Benign according to our data. Variant chr17-31318487-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 20 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014210.4. 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
	EVI2A	NM_014210.4	MANE Select	c.527A>G	p.Gln176Arg	missense	Exon 2 of 2	NP_055025.2
	NF1	NM_001042492.3	MANE Select	c.4836-7333T>C		intron	N/A	NP_001035957.1
	EVI2A	NM_001003927.3		c.596A>G	p.Gln199Arg	missense	Exon 3 of 3	NP_001003927.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVI2A	ENST00000462804.3	TSL:1 MANE Select	c.527A>G	p.Gln176Arg	missense	Exon 2 of 2	ENSP00000420557.3
	ENSG00000265118	ENST00000578584.5	TSL:2	c.299A>G	p.Gln100Arg	missense	Exon 1 of 3	ENSP00000463981.2
	NF1	ENST00000358273.9	TSL:1 MANE Select	c.4836-7333T>C		intron	N/A	ENSP00000351015.4

Frequencies

GnomAD3 genomes AF: 0.00247 AC: 376 AN: 152228 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00442

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00246 AC: 618 AN: 250880 AF XY: 0.00244

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.000436

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00444

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00501 AC: 7324 AN: 1461710 Hom.: 20 Cov.: 31 AF XY: 0.00487 AC XY: 3538 AN XY: 727152

African (AFR) AF: 0.00105 AC: 35 AN: 33468

American (AMR) AF: 0.000538 AC: 24 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.00180 AC: 47 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39682

South Asian (SAS) AF: 0.00136 AC: 117 AN: 86256

European-Finnish (FIN) AF: 0.000300 AC: 16 AN: 53406

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.00615 AC: 6843 AN: 1111972

Other (OTH) AF: 0.00391 AC: 236 AN: 60390

GnomAD4 genome AF: 0.00247 AC: 376 AN: 152346 Hom.: 1 Cov.: 32 AF XY: 0.00216 AC XY: 161 AN XY: 74506

African (AFR) AF: 0.00108 AC: 45 AN: 41582

American (AMR) AF: 0.000850 AC: 13 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4834

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00442 AC: 301 AN: 68030

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00387 Hom.: 2

Bravo AF: 0.00257

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00453 AC: 39

ExAC AF: 0.00235 AC: 285

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00469

EpiControl AF: 0.00439

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	EVI2A-related disorder (1)
-	-	1	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.011	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		1.4
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.12
Sift	Benign	0.73	T
Sift4G	Benign	0.70	T
Polyphen		0.73	P
Vest4		0.26
MVP		0.13
MPC		0.20
ClinPred		0.017	T
GERP RS		4.6
PromoterAI		-0.075	Neutral
Varity_R		0.12
gMVP		0.039
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs144778786; hg19: chr17-29645505; COSMIC: COSV99907749; COSMIC: COSV99907749;