rs1049688

Variant names:

• chr12-54292143-G-C
• rs1049688
• NM_001136023.3:c.*231C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001136023.3(NFE2):​c.*231C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000245 in 408,176 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: NFE2 NM_001136023.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.201
• Publications: 0 publications found

Genes affected

NFE2 (HGNC:7780): (nuclear factor, erythroid 2) Enables several functions, including WW domain binding activity; identical protein binding activity; and protein N-terminus binding activity. Contributes to cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to act upstream of or within several processes, including labyrinthine layer blood vessel development; negative regulation of bone mineralization; and negative regulation of syncytium formation by plasma membrane fusion. Part of protein-DNA complex. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000258344 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001136023.3. 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
	NFE2	NM_001136023.3	MANE Select	c.*231C>G		3_prime_UTR	Exon 3 of 3	NP_001129495.1
	NFE2	NM_001261461.2		c.*231C>G		3_prime_UTR	Exon 4 of 4	NP_001248390.1
	NFE2	NM_001400365.1		c.*231C>G		3_prime_UTR	Exon 3 of 3	NP_001387294.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFE2	ENST00000435572.7	TSL:1 MANE Select	c.*231C>G		3_prime_UTR	Exon 3 of 3	ENSP00000397185.2
	NFE2	ENST00000312156.8	TSL:1	c.*231C>G		3_prime_UTR	Exon 3 of 3	ENSP00000312436.4
	ENSG00000258344	ENST00000553061.1	TSL:5	n.545+14968G>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000245 AC: 1 AN: 408176 Hom.: 0 Cov.: 4 AF XY: 0.00 AC XY: 0 AN XY: 212436

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 11978

American (AMR) AF: 0.00 AC: 0 AN: 17318

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12848

East Asian (EAS) AF: 0.00 AC: 0 AN: 29574

South Asian (SAS) AF: 0.00 AC: 0 AN: 36096

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27490

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1840

European-Non Finnish (NFE) AF: 0.00000405 AC: 1 AN: 246888

Other (OTH) AF: 0.00 AC: 0 AN: 24144

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	5.4
DANN	Benign	0.80
PhyloP100		0.20
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs1049688; hg19: chr12-54685927;