chr17-31318976-T-C

Position:

• chr17-31318976-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_014210.4(EVI2A):​c.38A>G​(p.His13Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,612,420 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00097 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (2 hom.)
• Consequence: EVI2A NM_014210.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.777

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]

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020837277).
• BP6: Variant 17-31318976-T-C is Benign according to our data. Variant chr17-31318976-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 445615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EVI2A	NM_014210.4	c.38A>G	p.His13Arg	missense_variant	2/2	ENST00000462804.3
NF1	NM_001042492.3	c.4836-6844T>C		intron_variant		ENST00000358273.9
EVI2A	NM_001003927.3	c.107A>G	p.His36Arg	missense_variant	3/3
NF1	NM_000267.3	c.4773-6844T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EVI2A	ENST00000462804.3	c.38A>G	p.His13Arg	missense_variant	2/2	1	NM_014210.4	P2
NF1	ENST00000358273.9	c.4836-6844T>C		intron_variant		1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes AF: 0.000972 AC: 148 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00181

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00105 AC: 261 AN: 247920 Hom.: 1 AF XY: 0.00112 AC XY: 151 AN XY: 134316

Gnomad AFR exome AF: 0.000616

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00195

Gnomad OTH exome AF: 0.000986

GnomAD4 exome AF: 0.00165 AC: 2402 AN: 1460110 Hom.: 2 Cov.: 31 AF XY: 0.00159 AC XY: 1154 AN XY: 726424

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.00107

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00203

Gnomad4 OTH exome AF: 0.00128

GnomAD4 genome AF: 0.000972 AC: 148 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.000859 AC XY: 64 AN XY: 74480

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00181

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00144 Hom.: 2

Bravo AF: 0.00118

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.00115 AC: 140

EpiCase AF: 0.00169

EpiControl AF: 0.00166

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 18, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	NF1: BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T;.;T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.078
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.41	.;T;T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.021	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.6	M;.;M
MutationTaster	Benign	1.0	D;D;N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.9	D;D;.
REVEL	Benign	0.14
Sift	Uncertain	0.025	D;D;.
Sift4G	Benign	0.096	T;T;T
Polyphen		0.011	B;B;B
Vest4		0.24
MVP		0.27
MPC		0.029
ClinPred		0.012	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.23
gMVP		0.64

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

Publications

LitVar

Other links and lift over

dbSNP: rs144746834; hg19: chr17-29645994;