16-1839399-CAT-C

Variant names:

• chr16-1839399-CAT-C
• rs779513355
• NM_001163560.3:c.1072_1073delAT

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_001163560.3(MEIOB):​c.1072_1073delAT​(p.Met358ValfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,613,680 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: MEIOB NM_001163560.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 0.882
• Publications: 1 publications found

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

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 16-1839399-CAT-C is Pathogenic according to our data. Variant chr16-1839399-CAT-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2691781.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001163560.3. 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
	MEIOB	NM_001163560.3	MANE Select	c.1072_1073delAT	p.Met358ValfsTer12	frameshift	Exon 12 of 14	NP_001157032.1	Q8N635-2
	MEIOB	NM_152764.3		c.1072_1073delAT	p.Met358ValfsTer12	frameshift	Exon 12 of 13	NP_689977.2	Q8N635-1
	FAHD1	NM_001018104.3		c.*147_*148delAT		3_prime_UTR	Exon 3 of 3	NP_001018114.2	Q6P587-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEIOB	ENST00000325962.9	TSL:5 MANE Select	c.1072_1073delAT	p.Met358ValfsTer12	frameshift	Exon 12 of 14	ENSP00000314484.3	Q8N635-2
	FAHD1	ENST00000382668.8	TSL:1	c.*94_*95delAT		3_prime_UTR	Exon 2 of 2	ENSP00000372114.5	Q6P587-2
	MEIOB	ENST00000397344.7	TSL:5	c.1072_1073delAT	p.Met358ValfsTer12	frameshift	Exon 12 of 13	ENSP00000380504.3	Q8N635-1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000319 AC: 8 AN: 250862 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000246 AC: 36 AN: 1461436 Hom.: 0 AF XY: 0.0000248 AC XY: 18 AN XY: 726994

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39690

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86114

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

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

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1111856

Other (OTH) AF: 0.0000331 AC: 2 AN: 60382

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74440

African (AFR) AF: 0.00 AC: 0 AN: 41558

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000126 Hom.: 0

Bravo AF: 0.0000340

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Premature ovarian failure 23 (1)
1	-	-	Spermatogenic failure 22 (1)
1	-	-	Spermatogenic failure 22;C5882747:Premature ovarian failure 23 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.88
Mutation Taster		=36/164	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs779513355; hg19: chr16-1889400;