5-140548997-C-G

Variant names:

• chr5-140548997-C-G
• rs1051932137
• ENST00000532219.5:c.7771C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020690.6(ANKHD1-EIF4EBP3):​c.7771C>G​(p.Arg2591Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2591W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ANKHD1-EIF4EBP3 NM_020690.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.181
• Publications: 1 publications found

Genes affected

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]

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]

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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14629835).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020690.6. 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.195C>G	p.Pro65Pro	synonymous	Exon 2 of 3	NP_003723.1	O60516
	ANKHD1-EIF4EBP3	NM_020690.6		c.7771C>G	p.Arg2591Gly	missense	Exon 35 of 36	NP_065741.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKHD1-EIF4EBP3	ENST00000532219.5	TSL:2	c.7771C>G	p.Arg2591Gly	missense	Exon 35 of 36	ENSP00000432016.1
	EIF4EBP3	ENST00000310331.3	TSL:1 MANE Select	c.195C>G	p.Pro65Pro	synonymous	Exon 2 of 3	ENSP00000308472.2	O60516
	ANKHD1-EIF4EBP3	ENST00000437495.1	TSL:5	c.1828C>G	p.Arg610Gly	missense	Exon 7 of 8	ENSP00000396882.1	H7C0V5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248728 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000900

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461862 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727230

⚠️ 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: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60394

⚠️ 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

Alfa AF: 0.0000165 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	9.6
DANN	Uncertain	1.0
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.18
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.27	T
Vest4		0.47
MVP		0.12
MPC		0.50
ClinPred		0.92	D
GERP RS		-0.17
gMVP		0.093
Mutation Taster		=76/24	polymorphism

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: rs1051932137; hg19: chr5-139928582;