rs142962975

Variant names:

• chrX-71100917-G-A
• rs142962975
• NM_005938.4:c.687G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_005938.4(FOXO4):​c.687G>A​(p.Thr229Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000581 in 1,209,599 control chromosomes in the GnomAD database, including 2 homozygotes. There are 169 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., 81 hem., cov: 22)
  • Exomes 𝑓: 0.00034 (1 hom. 88 hem.)
• Consequence: FOXO4 NM_005938.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.308
• Publications: 1 publications found

Genes affected

FOXO4 (HGNC:7139): (forkhead box O4) This gene encodes a member of the O class of winged helix/forkhead transcription factor family. Proteins encoded by this class are regulated by factors involved in growth and differentiation indicating they play a role in these processes. A translocation involving this gene on chromosome X and the homolog of the Drosophila trithorax gene, encoding a DNA binding protein, located on chromosome 11 is associated with leukemia. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2010]

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant X-71100917-G-A is Benign according to our data. Variant chrX-71100917-G-A is described in ClinVar as [Benign]. Clinvar id is 788055.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.308 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 81 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXO4	NM_005938.4	c.687G>A	p.Thr229Thr	synonymous_variant	Exon 2 of 3	ENST00000374259.8	NP_005929.2
FOXO4	NM_001170931.2	c.522G>A	p.Thr174Thr	synonymous_variant	Exon 3 of 4		NP_001164402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXO4	ENST00000374259.8	c.687G>A	p.Thr229Thr	synonymous_variant	Exon 2 of 3	1	NM_005938.4	ENSP00000363377.3
FOXO4	ENST00000341558.4	c.522G>A	p.Thr174Thr	synonymous_variant	Exon 3 of 4	5		ENSP00000342209.3
FOXO4	ENST00000464598.1	n.*74G>A		downstream_gene_variant		2
FOXO4	ENST00000466874.1	n.*145G>A		downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00296 AC: 332 AN: 111976 Hom.: 1 Cov.: 22

Gnomad AFR AF: 0.0104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000564

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000565

Gnomad OTH AF: 0.00265

GnomAD2 exomes AF: 0.000929 AC: 165 AN: 177632 AF XY: 0.000542

Gnomad AFR exome AF: 0.0108

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000381

Gnomad OTH exome AF: 0.000455

GnomAD4 exome AF: 0.000337 AC: 370 AN: 1097569 Hom.: 1 Cov.: 33 AF XY: 0.000242 AC XY: 88 AN XY: 362945

African (AFR) AF: 0.0111 AC: 292 AN: 26393

American (AMR) AF: 0.000882 AC: 31 AN: 35152

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19360

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30181

South Asian (SAS) AF: 0.00 AC: 0 AN: 53998

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40477

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.0000143 AC: 12 AN: 841798

Other (OTH) AF: 0.000738 AC: 34 AN: 46076

GnomAD4 genome AF: 0.00297 AC: 333 AN: 112030 Hom.: 1 Cov.: 22 AF XY: 0.00237 AC XY: 81 AN XY: 34234

African (AFR) AF: 0.0104 AC: 320 AN: 30873

American (AMR) AF: 0.000563 AC: 6 AN: 10648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3547

South Asian (SAS) AF: 0.00 AC: 0 AN: 2664

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6132

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.0000565 AC: 3 AN: 53086

Other (OTH) AF: 0.00262 AC: 4 AN: 1528

Alfa AF: 0.00126 Hom.: 10

Bravo AF: 0.00352

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Apr 16, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.46
DANN	Benign	0.85
PhyloP100		-0.31
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs142962975; hg19: chrX-70320767;