Genetic Variant NM_002904.6:c.740G>A (chr6-31954557-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002904.6(NELFE):c.740G>A(p.Arg247His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000978 in 1,604,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R247C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000096 ( 0 hom. )

Consequence

NELFE
NM_002904.6 missense, splice_region

Scores

Splicing: ADA: 0.9430

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.90

Publications

2 publications found

Variant links:

Genes affected

NELFE (HGNC:13974): (negative elongation factor complex member E) The protein encoded by this gene is part of a complex termed negative elongation factor (NELF) which represses RNA polymerase II transcript elongation. This protein bears similarity to nuclear RNA-binding proteins; however, it has not been demonstrated that this protein binds RNA. The protein contains a tract of alternating basic and acidic residues, largely arginine (R) and aspartic acid (D). The gene localizes to the major histocompatibility complex (MHC) class III region on chromosome 6. [provided by RefSeq, Jul 2008]

NELFE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06949043).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002904.6. 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
	NELFE	NM_002904.6	MANE Select	c.740G>A	p.Arg247His	missense splice_region	Exon 7 of 11	NP_002895.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NELFE	ENST00000375429.8	TSL:1 MANE Select	c.740G>A	p.Arg247His	missense splice_region	Exon 7 of 11	ENSP00000364578.3	P18615-1
NELFE	ENST00000375425.9	TSL:2	c.761G>A	p.Arg254His	missense splice_region	Exon 7 of 11	ENSP00000364574.5	P18615-3
NELFE	ENST00000948308.1		c.758G>A	p.Arg253His	missense splice_region	Exon 8 of 12	ENSP00000618367.1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000156

AC:

AN:

243302

AF XY:

0.000213

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000914

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000964

AC:

140

AN:

1452484

Hom.:

Cov.:

AF XY:

0.000119

AC XY:

AN XY:

721346

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33402

American (AMR)

AF:

0.0000225

AC:

AN:

44382

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25364

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39622

South Asian (SAS)

AF:

0.000981

AC:

AN:

84604

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53060

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

0.0000416

AC:

AN:

1106316

Other (OTH)

AF:

0.000133

AC:

AN:

60010

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000112

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41510

American (AMR)

AF:

0.000196

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00145

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.531

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000117

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000198

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.12

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.062

MetaRNN

Benign

0.069

MetaSVM

Uncertain

-0.039

MutationAssessor

Uncertain

2.5

PhyloP100

2.9

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.2

REVEL

Benign

0.22

Sift

Uncertain

0.015

Sift4G

Benign

0.20

Polyphen

1.0

Vest4

0.37

MVP

0.79

MPC

0.69

ClinPred

0.20

GERP RS

5.3

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

Varity_R

0.11

gMVP

0.38

Mutation Taster

=60/40

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.94

dbscSNV1_RF

Pathogenic

0.80

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over