rs17201466

Variant names:

• chr6-31958823-C-T
• rs17201466
• NM_002904.6:c.-9+69G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002904.6(NELFE):​c.-9+69G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0306 in 659,354 control chromosomes in the GnomAD database, including 655 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (161 hom., cov: 33)
  • Exomes 𝑓: 0.030 (494 hom.)
• Consequence: NELFE NM_002904.6 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.258
• Publications: 8 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 6-31958823-C-T is Benign according to our data. Variant chr6-31958823-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 356299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0308 (4686/152308) while in subpopulation NFE AF = 0.0361 (2454/68034). AF 95% confidence interval is 0.0349. There are 161 homozygotes in GnomAd4. There are 2575 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 161 gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NELFE	NM_002904.6	MANE Select	c.-9+69G>A		intron	N/A	NP_002895.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NELFE	ENST00000375429.8	TSL:1 MANE Select	c.-9+69G>A		intron	N/A	ENSP00000364578.3
	NELFE	ENST00000375425.9	TSL:2	c.-140G>A		5_prime_UTR	Exon 1 of 11	ENSP00000364574.5
	NELFE	ENST00000948309.1		c.-252G>A		5_prime_UTR	Exon 1 of 11	ENSP00000618368.1

Frequencies

GnomAD3 genomes AF: 0.0308 AC: 4686 AN: 152190 Hom.: 161 Cov.: 33

Gnomad AFR AF: 0.00627

Gnomad AMI AF: 0.0857

Gnomad AMR AF: 0.0124

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0122

Gnomad FIN AF: 0.150

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0361

Gnomad OTH AF: 0.0177

GnomAD4 exome AF: 0.0305 AC: 15464 AN: 507046 Hom.: 494 Cov.: 0 AF XY: 0.0290 AC XY: 7917 AN XY: 273324

African (AFR) AF: 0.00545 AC: 77 AN: 14122

American (AMR) AF: 0.00955 AC: 264 AN: 27652

Ashkenazi Jewish (ASJ) AF: 0.00304 AC: 51 AN: 16750

East Asian (EAS) AF: 0.000189 AC: 6 AN: 31746

South Asian (SAS) AF: 0.00955 AC: 537 AN: 56244

European-Finnish (FIN) AF: 0.130 AC: 4121 AN: 31726

Middle Eastern (MID) AF: 0.00809 AC: 30 AN: 3708

European-Non Finnish (NFE) AF: 0.0328 AC: 9717 AN: 296530

Other (OTH) AF: 0.0231 AC: 661 AN: 28568

GnomAD4 genome AF: 0.0308 AC: 4686 AN: 152308 Hom.: 161 Cov.: 33 AF XY: 0.0346 AC XY: 2575 AN XY: 74464

African (AFR) AF: 0.00626 AC: 260 AN: 41566

American (AMR) AF: 0.0124 AC: 190 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.000964 AC: 5 AN: 5186

South Asian (SAS) AF: 0.0124 AC: 60 AN: 4832

European-Finnish (FIN) AF: 0.150 AC: 1592 AN: 10592

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0361 AC: 2454 AN: 68034

Other (OTH) AF: 0.0175 AC: 37 AN: 2114

Alfa AF: 0.0303 Hom.: 110

Bravo AF: 0.0191

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Trichohepatoenteric syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	7.5
DANN	Benign	0.86
PhyloP100		0.26
PromoterAI		-0.063	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	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: rs17201466; hg19: chr6-31926600;