22-31944712-G-T

Variant names:

• chr22-31944712-G-T
• rs11539379
• NM_003405.4:c.-22G>T

Variant summary

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

The NM_003405.4(YWHAH):​c.-22G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000816 in 1,225,290 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: 33)
  • Exomes 𝑓: 8.2e-7 (0 hom.)
• Consequence: YWHAH NM_003405.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.927
• Publications: 3 publications found

Genes affected

YWHAH (HGNC:12853): (tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein eta) This gene product belongs to the 14-3-3 family of proteins which mediate signal transduction by binding to phosphoserine-containing proteins. This highly conserved protein family is found in both plants and mammals, and this protein is 99% identical to the mouse, rat and bovine orthologs. This gene contains a 7 bp repeat sequence in its 5' UTR, and changes in the number of this repeat have been associated with early-onset schizophrenia and psychotic bipolar disorder. [provided by RefSeq, Jun 2009]

ENSG00000285404 (HGNC:):

YWHAH-AS1 (HGNC:23051): (YWHAH antisense RNA 1) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

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=-0.68).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
YWHAH	NM_003405.4	c.-22G>T		5_prime_UTR_variant	Exon 1 of 2	ENST00000248975.6	NP_003396.1
YWHAH-AS1	NR_126507.1	n.130+521C>A		intron_variant	Intron 1 of 2
YWHAH-AS1	NR_171018.1	n.134+521C>A		intron_variant	Intron 1 of 2
LOC124900477	XR_007068065.1	n.-122G>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
YWHAH	ENST00000248975.6	c.-22G>T		5_prime_UTR_variant	Exon 1 of 2	1	NM_003405.4	ENSP00000248975.5
ENSG00000285404	ENST00000646701.1	c.1787-11427G>T		intron_variant	Intron 20 of 20			ENSP00000496158.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.16e-7 AC: 1 AN: 1225290 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 603250

⚠️ 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: 24940

American (AMR) AF: 0.00 AC: 0 AN: 23908

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19768

East Asian (EAS) AF: 0.00 AC: 0 AN: 24338

South Asian (SAS) AF: 0.00 AC: 0 AN: 63502

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28508

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3544

European-Non Finnish (NFE) AF: 0.00000101 AC: 1 AN: 988566

Other (OTH) AF: 0.00 AC: 0 AN: 48216

⚠️ 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.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	16
DANN	Benign	0.94
PhyloP100		0.93
PromoterAI		0.0043	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0

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: rs11539379; hg19: chr22-32340698;