NM_002904.6:c.739C>T

Variant names:

• chr6-31954558-G-A
• rs375169736
• NM_002904.6:c.739C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002904.6(NELFE):​c.739C>T​(p.Arg247Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000199 in 1,605,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. R247H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: NELFE NM_002904.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.81
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34830272).

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.739C>T	p.Arg247Cys	missense	Exon 7 of 11	NP_002895.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NELFE	ENST00000375429.8	TSL:1 MANE Select	c.739C>T	p.Arg247Cys	missense	Exon 7 of 11	ENSP00000364578.3	P18615-1
	NELFE	ENST00000375425.9	TSL:2	c.760C>T	p.Arg254Cys	missense	Exon 7 of 11	ENSP00000364574.5	P18615-3
	NELFE	ENST00000948308.1		c.757C>T	p.Arg253Cys	missense	Exon 8 of 12	ENSP00000618367.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152042 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000327 AC: 8 AN: 244620 AF XY: 0.0000152

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000204

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000206 AC: 30 AN: 1453792 Hom.: 0 Cov.: 34 AF XY: 0.0000194 AC XY: 14 AN XY: 722168

African (AFR) AF: 0.0000299 AC: 1 AN: 33424

American (AMR) AF: 0.000135 AC: 6 AN: 44462

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25464

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.0000707 AC: 6 AN: 84894

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53100

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1107030

Other (OTH) AF: 0.0000500 AC: 3 AN: 60054

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152042 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74266

African (AFR) AF: 0.0000242 AC: 1 AN: 41326

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000247 AC: 3

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	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.35	T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.8
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.062	T
Polyphen		1.0	D
Vest4		0.60
MVP		0.68
MPC		0.76
ClinPred		0.38	T
GERP RS		5.3
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.16
gMVP		0.44
Mutation Taster		=48/52	disease causing

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: rs375169736; hg19: chr6-31922335;