5-140548543-C-T

Variant names:

• chr5-140548543-C-T
• rs250425
• NM_003732.3:c.104-363C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003732.3(EIF4EBP3):​c.104-363C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 152,098 control chromosomes in the GnomAD database, including 3,326 homozygotes. 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: 𝑓 0.19 (3326 hom., cov: 32)
• Consequence: EIF4EBP3 NM_003732.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0680
• Publications: 11 publications found

Genes affected

EIF4EBP3 (HGNC:3290): (eukaryotic translation initiation factor 4E binding protein 3) This gene encodes a member of the EIF4EBP family, which consists of proteins that bind to eukaryotic translation initiation factor 4E and regulate its assembly into EIF4F, the multi-subunit translation initiation factor that recognizes the mRNA cap structure. Read-through transcription from the neighboring upstream gene (MASK or ANKHD1) generates a transcript (MASK-BP3) that encodes a protein comprised of the MASK protein sequence for the majority of the protein and a different C-terminus due to an alternate reading frame for the EIF4EBP3 segments. [provided by RefSeq, Oct 2010]

ANKHD1-EIF4EBP3 (HGNC:33530): (ANKHD1-EIF4EBP3 readthrough) The ANKHD1-EIF4EBP3 mRNA is an infrequent but naturally occurring readthrough transcript of the neighboring ANKHD1 and EIF4EBP3 genes. This readthrough transcript encodes a protein composed mostly of the multiple ankyrin repeats, single KH-domain protein, with its C-terminus encoded in a different reading frame from the shared portion of the EIF4EBP3 gene. The significance of this readthrough mRNA and the function of its protein product have not yet been determined. [provided by RefSeq, Nov 2009]

SRA1 (HGNC:11281): (steroid receptor RNA activator 1) Both long non-coding and protein-coding RNAs are transcribed from this gene, and they represent alternatively spliced transcript variants. This gene was initially defined as a non-coding RNA, which is a coactivator for several nuclear receptors (NRs) and is associated with breast cancer. It has now been found that this gene is involved in the regulation of many NR and non-NR activities, including metabolism, adipogenesis and chromatin organization. The long non-coding RNA transcripts interact with a variety of proteins, including the protein encoded by this gene. The encoded protein acts as a transcriptional repressor by binding to the non-coding RNA. [provided by RefSeq, Mar 2012]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.261 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003732.3. 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
	EIF4EBP3	NM_003732.3	MANE Select	c.104-363C>T		intron	N/A	NP_003723.1	O60516
	ANKHD1-EIF4EBP3	NM_020690.6		c.7680-363C>T		intron	N/A	NP_065741.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF4EBP3	ENST00000310331.3	TSL:1 MANE Select	c.104-363C>T		intron	N/A	ENSP00000308472.2	O60516
	ANKHD1-EIF4EBP3	ENST00000532219.5	TSL:2	c.7680-363C>T		intron	N/A	ENSP00000432016.1
	ANKHD1-EIF4EBP3	ENST00000437495.1	TSL:5	c.1737-363C>T		intron	N/A	ENSP00000396882.1	H7C0V5

Frequencies

GnomAD3 genomes AF: 0.194 AC: 29412 AN: 151980 Hom.: 3318 Cov.: 32

Gnomad AFR AF: 0.0890

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.216

Gnomad ASJ AF: 0.200

Gnomad EAS AF: 0.272

Gnomad SAS AF: 0.265

Gnomad FIN AF: 0.268

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.231

Gnomad OTH AF: 0.195

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.193 AC: 29429 AN: 152098 Hom.: 3326 Cov.: 32 AF XY: 0.196 AC XY: 14562 AN XY: 74340

African (AFR) AF: 0.0888 AC: 3688 AN: 41528

American (AMR) AF: 0.217 AC: 3313 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 695 AN: 3470

East Asian (EAS) AF: 0.273 AC: 1404 AN: 5150

South Asian (SAS) AF: 0.265 AC: 1274 AN: 4816

European-Finnish (FIN) AF: 0.268 AC: 2832 AN: 10570

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.231 AC: 15706 AN: 67972

Other (OTH) AF: 0.197 AC: 417 AN: 2112

Alfa AF: 0.214 Hom.: 9892

Bravo AF: 0.183

Asia WGS AF: 0.286 AC: 996 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	8.8
DANN	Benign	0.43
PhyloP100		-0.068
Mutation Taster		=100/0	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: rs250425; hg19: chr5-139928128;