4-1983860-G-A

Position:

• chr4-1983860-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005663.5(NELFA):​c.1290C>T​(p.Asn430Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00777 in 1,576,208 control chromosomes in the GnomAD database, including 96 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0070 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0078 (89 hom.)
• Consequence: NELFA NM_005663.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.63

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 4-1983860-G-A is Benign according to our data. Variant chr4-1983860-G-A is described in ClinVar as [Benign]. Clinvar id is 788777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.63 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00784 (11167/1423858) while in subpopulation MID AF= 0.0379 (211/5564). AF 95% confidence interval is 0.0337. There are 89 homozygotes in gnomad4_exome. There are 5743 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NELFA	NM_005663.5	c.1290C>T	p.Asn430Asn	synonymous_variant	9/11	ENST00000382882.9	NP_005654.4
NELFA	XM_017008589.3	c.1374C>T	p.Asn458Asn	synonymous_variant	10/12		XP_016864078.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NELFA	ENST00000382882.9	c.1290C>T	p.Asn430Asn	synonymous_variant	9/11	1	NM_005663.5	ENSP00000372335.4

Frequencies

GnomAD3 genomes AF: 0.00705 AC: 1073 AN: 152232 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00961

Gnomad ASJ AF: 0.0435

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00662

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.00913

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00817 AC: 1783 AN: 218272 Hom.: 17 AF XY: 0.00873 AC XY: 1019 AN XY: 116670

Gnomad AFR exome AF: 0.00157

Gnomad AMR exome AF: 0.00619

Gnomad ASJ exome AF: 0.0424

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00599

Gnomad FIN exome AF: 0.00170

Gnomad NFE exome AF: 0.0106

Gnomad OTH exome AF: 0.0125

GnomAD4 exome AF: 0.00784 AC: 11167 AN: 1423858 Hom.: 89 Cov.: 32 AF XY: 0.00815 AC XY: 5743 AN XY: 704416

Gnomad4 AFR exome AF: 0.00255

Gnomad4 AMR exome AF: 0.00645

Gnomad4 ASJ exome AF: 0.0397

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00711

Gnomad4 FIN exome AF: 0.00217

Gnomad4 NFE exome AF: 0.00770

Gnomad4 OTH exome AF: 0.0103

GnomAD4 genome AF: 0.00704 AC: 1073 AN: 152350 Hom.: 7 Cov.: 33 AF XY: 0.00669 AC XY: 498 AN XY: 74484

Gnomad4 AFR AF: 0.00159

Gnomad4 AMR AF: 0.00960

Gnomad4 ASJ AF: 0.0435

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00662

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00911

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00974 Hom.: 6

Bravo AF: 0.00727

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	NELFA: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	3.8
DANN	Benign	0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs1139902; hg19: chr4-1985587;