16-1839439-C-A

Variant names:

• chr16-1839439-C-A
• rs972548876
• ENST00000382668.8:c.*133C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_001163560.3(MEIOB):​c.1035-1G>T variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000000689 in 1,451,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MEIOB NM_001163560.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.43
• Publications: 0 publications found

Genes affected

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]

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]

MEIOB Gene-Disease associations (from GenCC):

• spermatogenic failure 22

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.1299435 fraction of the gene. Cryptic splice site detected, with MaxEntScore 11, offset of 6, new splice context is: ttgtttcttttcatttccAGctg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

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.1035-1G>T		splice_acceptor intron	N/A	NP_001157032.1	Q8N635-2
	FAHD1	NM_001018104.3		c.*186C>A		3_prime_UTR	Exon 3 of 3	NP_001018114.2	Q6P587-3
	FAHD1	NM_001142398.2		c.*133C>A		3_prime_UTR	Exon 2 of 2	NP_001135870.2	Q6P587-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAHD1	ENST00000382668.8	TSL:1	c.*133C>A		3_prime_UTR	Exon 2 of 2	ENSP00000372114.5	Q6P587-2
	MEIOB	ENST00000325962.9	TSL:5 MANE Select	c.1035-1G>T		splice_acceptor intron	N/A	ENSP00000314484.3	Q8N635-2
	FAHD1	ENST00000382666.6	TSL:2	c.*186C>A		3_prime_UTR	Exon 3 of 3	ENSP00000372112.5	Q6P587-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451402 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 721546

African (AFR) AF: 0.0000304 AC: 1 AN: 32906

American (AMR) AF: 0.00 AC: 0 AN: 42116

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25592

East Asian (EAS) AF: 0.00 AC: 0 AN: 39580

South Asian (SAS) AF: 0.00 AC: 0 AN: 84236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53254

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108018

Other (OTH) AF: 0.00 AC: 0 AN: 60010

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.89	D
PhyloP100		5.4
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.90		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.88		Position offset: -7
DS_AL_spliceai		0.90		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs972548876; hg19: chr16-1889440;