rs1077020

Positions:

• chr4-1986466-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005663.5(NELFA):​c.635-64A>G variant causes a intron 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 NM_005663.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.54

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

Verdict is Benign. Variant got -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/exons	MANE	UniProt
NELFA	NM_005663.5	c.635-64A>G		intron_variant		ENST00000382882.9
MIR943	NR_030641.1	n.12A>G		non_coding_transcript_exon_variant	1/1
NELFA	XM_017008589.3	c.719-64A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NELFA	ENST00000382882.9	c.635-64A>G		intron_variant		1	NM_005663.5	P1
MIR943	ENST00000401286.1	n.12A>G		non_coding_transcript_exon_variant	1/1

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

GnomAD3 exomes AF: 0.208 AC: 49362 AN: 237856 Hom.: 5340 AF XY: 0.201 AC XY: 25984 AN XY: 129168

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 SAS exome AF: 0.127

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

Gnomad4 AFR exome AF: 0.367

Gnomad4 AMR exome AF: 0.224

Gnomad4 ASJ exome AF: 0.251

Gnomad4 EAS exome AF: 0.261

Gnomad4 SAS exome AF: 0.131

Gnomad4 FIN exome AF: 0.167

Gnomad4 NFE exome AF: 0.216

Gnomad4 OTH exome AF: 0.228

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

Gnomad4 AFR AF: 0.367

Gnomad4 AMR AF: 0.235

Gnomad4 ASJ AF: 0.261

Gnomad4 EAS AF: 0.247

Gnomad4 SAS AF: 0.129

Gnomad4 FIN AF: 0.163

Gnomad4 NFE AF: 0.214

Gnomad4 OTH AF: 0.248

Alfa AF: 0.234 Hom.: 3909

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

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

Publications

LitVar

Other links and lift over

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