8-100922743-T-C

Variant names:

• chr8-100922743-T-C
• rs4734497
• NM_145690.3:c.678+1212A>G

Variant summary

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

The NM_145690.3(YWHAZ):​c.678+1212A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 152,126 control chromosomes in the GnomAD database, including 5,881 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 0.27 (5878 hom., cov: 32)
  • Exomes 𝑓: 0.33 (3 hom.)
• Consequence: YWHAZ NM_145690.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.585
• Publications: 13 publications found

Genes affected

YWHAZ (HGNC:12855): (tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta) 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 sheep orthologs. The encoded protein interacts with IRS1 protein, suggesting a role in regulating insulin sensitivity. Several transcript variants that differ in the 5' UTR but that encode the same protein have been identified for this gene. [provided by RefSeq, Oct 2008]

YWHAZ Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics, Illumina

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.322 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145690.3. 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
	YWHAZ	NM_145690.3	MANE Select	c.678+1212A>G		intron	N/A	NP_663723.1
	YWHAZ	NM_001135699.2		c.678+1212A>G		intron	N/A	NP_001129171.1
	YWHAZ	NM_001135700.2		c.678+1212A>G		intron	N/A	NP_001129172.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	YWHAZ	ENST00000395958.6	TSL:1 MANE Select	c.678+1212A>G		intron	N/A	ENSP00000379288.2
	YWHAZ	ENST00000353245.7	TSL:1	c.678+1212A>G		intron	N/A	ENSP00000309503.3
	YWHAZ	ENST00000395956.7	TSL:1	c.678+1212A>G		intron	N/A	ENSP00000379286.3

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40795 AN: 151984 Hom.: 5873 Cov.: 32

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.352

Gnomad AMR AF: 0.260

Gnomad ASJ AF: 0.253

Gnomad EAS AF: 0.138

Gnomad SAS AF: 0.272

Gnomad FIN AF: 0.307

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.326

Gnomad OTH AF: 0.267

GnomAD4 exome AF: 0.333 AC: 8 AN: 24 Hom.: 3 Cov.: 0 AF XY: 0.357 AC XY: 5 AN XY: 14

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.400 AC: 8 AN: 20

Other (OTH) AF: 0.00 AC: 0 AN: 2

⚠️ 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 AF: 0.268 AC: 40807 AN: 152102 Hom.: 5878 Cov.: 32 AF XY: 0.265 AC XY: 19707 AN XY: 74346

African (AFR) AF: 0.183 AC: 7596 AN: 41496

American (AMR) AF: 0.260 AC: 3977 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.253 AC: 876 AN: 3468

East Asian (EAS) AF: 0.138 AC: 716 AN: 5178

South Asian (SAS) AF: 0.273 AC: 1317 AN: 4824

European-Finnish (FIN) AF: 0.307 AC: 3241 AN: 10546

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.326 AC: 22134 AN: 67990

Other (OTH) AF: 0.264 AC: 557 AN: 2112

Alfa AF: 0.308 Hom.: 20684

Bravo AF: 0.264

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.9
DANN	Benign	0.63
PhyloP100		-0.58
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: rs4734497; hg19: chr8-101934971;