4-47875296-G-C

Variant names:

• chr4-47875296-G-C
• rs61747431
• NM_001278624.2:c.2080-3C>G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_001278624.2(NFXL1):​c.2080-3C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,605,156 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0065 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (4 hom.)
• Consequence: NFXL1 NM_001278624.2 splice_region, intron
• Scores: Splicing: ADA: 0.9977
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.444

Genes affected

NFXL1 (HGNC:18726): (nuclear transcription factor, X-box binding like 1) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription, DNA-templated. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000282917 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 4-47875296-G-C is Benign according to our data. Variant chr4-47875296-G-C is described in ClinVar as [Benign]. Clinvar id is 3042907.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00653 (993/152138) while in subpopulation AFR AF= 0.0215 (894/41502). AF 95% confidence interval is 0.0204. There are 6 homozygotes in gnomad4. There are 493 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFXL1	NM_001278624.2	c.2080-3C>G		splice_region_variant, intron_variant	Intron 17 of 22	ENST00000507489.2	NP_001265553.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFXL1	ENST00000507489.2	c.2080-3C>G		splice_region_variant, intron_variant	Intron 17 of 22	1	NM_001278624.2	ENSP00000422037.1

Frequencies

GnomAD3 genomes AF: 0.00654 AC: 994 AN: 152020 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0216

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00426

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.00163 AC: 398 AN: 244440 Hom.: 1 AF XY: 0.00125 AC XY: 165 AN XY: 132096

Gnomad AFR exome AF: 0.0208

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.000103

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000339

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000162

Gnomad OTH exome AF: 0.000505

GnomAD4 exome AF: 0.000690 AC: 1003 AN: 1453018 Hom.: 4 Cov.: 29 AF XY: 0.000594 AC XY: 429 AN XY: 722610

Gnomad4 AFR exome AF: 0.0216

Gnomad4 AMR exome AF: 0.00161

Gnomad4 ASJ exome AF: 0.0000387

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000235

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000831

Gnomad4 OTH exome AF: 0.00178

GnomAD4 genome AF: 0.00653 AC: 993 AN: 152138 Hom.: 6 Cov.: 32 AF XY: 0.00663 AC XY: 493 AN XY: 74382

Gnomad4 AFR AF: 0.0215

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.00172 Hom.: 0

Bravo AF: 0.00801

Asia WGS AF: 0.000578 AC: 2 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

NFXL1-related disorder Benign:1

Apr 26, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	17
DANN	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.77		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.77		Position offset: -3

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

Publications

LitVar

Other links and lift over

dbSNP: rs61747431; hg19: chr4-47877313;