4-1986466-T-C

Variant names:

• chr4-1986466-T-C
• rs1077020
• ENST00000467661.5:n.95A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000467661.5(NELFA):​n.95A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 1,606,562 control chromosomes in the GnomAD database, including 40,340 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.25 (5340 hom., cov: 33)
  • Exomes 𝑓: 0.22 (35000 hom.)
• Consequence: NELFA ENST00000467661.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.54
• Publications: 30 publications found

Genes affected

NELFA (HGNC:12768): (negative elongation factor complex member A) This gene is expressed ubiquitously with higher levels in fetal than in adult tissues. It encodes a protein sharing 93% sequence identity with the mouse protein. Wolf-Hirschhorn syndrome (WHS) is a malformation syndrome associated with a hemizygous deletion of the distal short arm of chromosome 4. This gene is mapped to the 165 kb WHS critical region, and may play a role in the phenotype of the WHS or Pitt-Rogers-Danks syndrome. The encoded protein is found to be capable of reacting with HLA-A2-restricted and tumor-specific cytotoxic T lymphocytes, suggesting a target for use in specific immunotherapy for a large number of cancer patients. This protein has also been shown to be a member of the NELF (negative elongation factor) protein complex that participates in the regulation of RNA polymerase II transcription elongation. [provided by RefSeq, Jul 2008]

MIR943 (HGNC:33689): (microRNA 943) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.362 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NELFA	NM_005663.5	c.635-64A>G		intron_variant	Intron 4 of 10	ENST00000382882.9	NP_005654.4
MIR943	NR_030641.1	n.12A>G		non_coding_transcript_exon_variant	Exon 1 of 1
NELFA	XM_017008589.3	c.719-64A>G		intron_variant	Intron 5 of 11		XP_016864078.2
MIR943	unassigned_transcript_724	n.-43A>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NELFA	ENST00000382882.9	c.635-64A>G		intron_variant	Intron 4 of 10	1	NM_005663.5	ENSP00000372335.4

Frequencies

GnomAD3 genomes AF: 0.255 AC: 38603 AN: 151672 Hom.: 5320 Cov.: 33

Gnomad AFR AF: 0.366

Gnomad AMI AF: 0.336

Gnomad AMR AF: 0.235

Gnomad ASJ AF: 0.261

Gnomad EAS AF: 0.248

Gnomad SAS AF: 0.130

Gnomad FIN AF: 0.163

Gnomad MID AF: 0.172

Gnomad NFE AF: 0.214

Gnomad OTH AF: 0.248

GnomAD2 exomes AF: 0.208 AC: 49362 AN: 237856 AF XY: 0.201

Gnomad AFR exome AF: 0.352

Gnomad AMR exome AF: 0.216

Gnomad ASJ exome AF: 0.251

Gnomad EAS exome AF: 0.238

Gnomad FIN exome AF: 0.158

Gnomad NFE exome AF: 0.207

Gnomad OTH exome AF: 0.212

GnomAD4 exome AF: 0.216 AC: 313524 AN: 1454770 Hom.: 35000 Cov.: 32 AF XY: 0.212 AC XY: 153173 AN XY: 723204

African (AFR) AF: 0.367 AC: 12231 AN: 33282

American (AMR) AF: 0.224 AC: 9858 AN: 44032

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 6511 AN: 25948

East Asian (EAS) AF: 0.261 AC: 10285 AN: 39462

South Asian (SAS) AF: 0.131 AC: 11091 AN: 84782

European-Finnish (FIN) AF: 0.167 AC: 8747 AN: 52444

Middle Eastern (MID) AF: 0.181 AC: 1033 AN: 5694

European-Non Finnish (NFE) AF: 0.216 AC: 240095 AN: 1109026

Other (OTH) AF: 0.228 AC: 13673 AN: 60100

GnomAD4 genome AF: 0.255 AC: 38675 AN: 151792 Hom.: 5340 Cov.: 33 AF XY: 0.250 AC XY: 18519 AN XY: 74176

African (AFR) AF: 0.367 AC: 15145 AN: 41318

American (AMR) AF: 0.235 AC: 3597 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 904 AN: 3470

East Asian (EAS) AF: 0.247 AC: 1274 AN: 5150

South Asian (SAS) AF: 0.129 AC: 621 AN: 4808

European-Finnish (FIN) AF: 0.163 AC: 1721 AN: 10552

Middle Eastern (MID) AF: 0.175 AC: 51 AN: 292

European-Non Finnish (NFE) AF: 0.214 AC: 14533 AN: 67900

Other (OTH) AF: 0.248 AC: 524 AN: 2110

Alfa AF: 0.236 Hom.: 6339

Bravo AF: 0.269

Asia WGS AF: 0.241 AC: 837 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.6
DANN	Benign	0.56
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs1077020; hg19: chr4-1988193; COSMIC: COSV56388603; COSMIC: COSV56388603;