16-1839264-CAA-C

Variant names:

• chr16-1839264-CAA-C
• rs745502213
• NM_001163560.3:c.1207_1208delTT

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PVS1 PM2 PP5_Moderate BS1_Supporting

The NM_001163560.3(MEIOB):​c.1207_1208delTT​(p.Leu403GlyfsTer6) variant causes a frameshift change. The variant allele was found at a frequency of 0.000212 in 1,605,570 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: MEIOB NM_001163560.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.42

Genes affected

MEIOB (HGNC:28569): (meiosis specific with OB-fold) Predicted to enable chromatin binding activity; single-stranded DNA 3'-5' exodeoxyribonuclease activity; and single-stranded DNA binding activity. Predicted to be involved in double-strand break repair via homologous recombination; fertilization; and meiotic nuclear division. Predicted to be located in cytoplasm. Implicated in spermatogenic failure 22. [provided by Alliance of Genome Resources, Apr 2022]

FAHD1 (HGNC:14169): (fumarylacetoacetate hydrolase domain containing 1) Enables acetylpyruvate hydrolase activity; fumarylpyruvate hydrolase activity; and oxaloacetate decarboxylase activity. Located in cytosol; mitochondrion; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-1839264-CAA-C is Pathogenic according to our data. Variant chr16-1839264-CAA-C is described in ClinVar as [Pathogenic]. Clinvar id is 2078114.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000222 (323/1453414) while in subpopulation NFE AF= 0.000277 (307/1108634). AF 95% confidence interval is 0.000251. There are 0 homozygotes in gnomad4_exome. There are 167 alleles in male gnomad4_exome subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEIOB	NM_001163560.3	c.1207_1208delTT	p.Leu403GlyfsTer6	frameshift_variant	Exon 12 of 14	ENST00000325962.9	NP_001157032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEIOB	ENST00000325962.9	c.1207_1208delTT	p.Leu403GlyfsTer6	frameshift_variant	Exon 12 of 14	5	NM_001163560.3	ENSP00000314484.3

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.000206

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000696 AC: 17 AN: 244296 Hom.: 0 AF XY: 0.0000758 AC XY: 10 AN XY: 131970

Gnomad AFR exome AF: 0.0000622

Gnomad AMR exome AF: 0.0000612

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000126

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000222 AC: 323 AN: 1453414 Hom.: 0 AF XY: 0.000231 AC XY: 167 AN XY: 722438

Gnomad4 AFR exome AF: 0.0000302

Gnomad4 AMR exome AF: 0.0000466

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000277

Gnomad4 OTH exome AF: 0.000217

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74334

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000831

EpiCase AF: 0.000329

EpiControl AF: 0.000297

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jun 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Leu403Glyfs*6) in the MEIOB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MEIOB are known to be pathogenic (PMID: 30838384). This variant is present in population databases (rs745502213, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with MEIOB-related conditions. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs745502213; hg19: chr16-1889265;