rs3034718

Variant names:

• chr4-1986461-C-CCT
• rs3034718
• NM_005663.5:c.635-60_635-59insAG

Your query was ambiguous. Multiple possible variants found:

• chr4-1986461-C-CCT
• chr4-1986461-C-CT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_005663.5(NELFA):​c.635-60_635-59insAG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 1,608,472 control chromosomes in the GnomAD database, including 42,970 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.27 (6426 hom., cov: 22)
  • Exomes 𝑓: 0.22 (36544 hom.)
• Consequence: NELFA NM_005663.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.292
• Publications: 7 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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.423 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005663.5. 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
	NELFA	NM_005663.5	MANE Select	c.635-60_635-59insAG		intron	N/A	NP_005654.4
	MIR943	NR_030641.1		n.16_17insAG		non_coding_transcript_exon	Exon 1 of 1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NELFA	ENST00000382882.9	TSL:1 MANE Select	c.635-60_635-59insAG		intron	N/A	ENSP00000372335.4	Q9H3P2-1
	NELFA	ENST00000542778.5	TSL:1	c.668-60_668-59insAG		intron	N/A	ENSP00000445757.2	A0A0C4DFX9
	NELFA	ENST00000467661.5	TSL:1	n.99_100insAG		non_coding_transcript_exon	Exon 1 of 7

Frequencies

GnomAD3 genomes AF: 0.273 AC: 41533 AN: 151894 Hom.: 6405 Cov.: 22

Gnomad AFR AF: 0.427

Gnomad AMI AF: 0.337

Gnomad AMR AF: 0.244

Gnomad ASJ AF: 0.260

Gnomad EAS AF: 0.264

Gnomad SAS AF: 0.135

Gnomad FIN AF: 0.162

Gnomad MID AF: 0.185

Gnomad NFE AF: 0.215

Gnomad OTH AF: 0.264

GnomAD2 exomes AF: 0.216 AC: 51654 AN: 239416 AF XY: 0.208

Gnomad AFR exome AF: 0.417

Gnomad AMR exome AF: 0.221

Gnomad ASJ exome AF: 0.252

Gnomad EAS exome AF: 0.254

Gnomad FIN exome AF: 0.159

Gnomad NFE exome AF: 0.210

Gnomad OTH exome AF: 0.220

GnomAD4 exome AF: 0.219 AC: 318932 AN: 1456460 Hom.: 36544 Cov.: 32 AF XY: 0.215 AC XY: 155797 AN XY: 724210

African (AFR) AF: 0.430 AC: 14342 AN: 33350

American (AMR) AF: 0.228 AC: 10101 AN: 44230

Ashkenazi Jewish (ASJ) AF: 0.252 AC: 6538 AN: 25982

East Asian (EAS) AF: 0.282 AC: 11160 AN: 39524

South Asian (SAS) AF: 0.138 AC: 11692 AN: 85028

European-Finnish (FIN) AF: 0.167 AC: 8766 AN: 52546

Middle Eastern (MID) AF: 0.203 AC: 1162 AN: 5718

European-Non Finnish (NFE) AF: 0.217 AC: 241098 AN: 1109918

Other (OTH) AF: 0.234 AC: 14073 AN: 60164

GnomAD4 genome AF: 0.274 AC: 41608 AN: 152012 Hom.: 6426 Cov.: 22 AF XY: 0.267 AC XY: 19871 AN XY: 74296

African (AFR) AF: 0.428 AC: 17712 AN: 41404

American (AMR) AF: 0.244 AC: 3735 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.260 AC: 904 AN: 3472

East Asian (EAS) AF: 0.263 AC: 1358 AN: 5154

South Asian (SAS) AF: 0.134 AC: 647 AN: 4824

European-Finnish (FIN) AF: 0.162 AC: 1721 AN: 10598

Middle Eastern (MID) AF: 0.185 AC: 54 AN: 292

European-Non Finnish (NFE) AF: 0.215 AC: 14614 AN: 67958

Other (OTH) AF: 0.264 AC: 558 AN: 2112

Alfa AF: 0.243 Hom.: 802

Bravo AF: 0.290

Asia WGS AF: 0.255 AC: 884 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.29
Mutation Taster		=44/56	disease causing

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3034718; hg19: chr4-1988188; COSMIC: COSV104393813; COSMIC: COSV104393813;