chr16-1839256-G-T

Variant names:

• chr16-1839256-G-T
• rs377366231
• NM_001163560.3:c.1217C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001163560.3(MEIOB):​c.1217C>A​(p.Thr406Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000697 in 1,434,014 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T406M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: MEIOB NM_001163560.3 missense, splice_region
• Scores: Splicing: ADA: 0.9638
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.06
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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.1217C>A	p.Thr406Lys	missense splice_region	Exon 12 of 14	NP_001157032.1	Q8N635-2
	MEIOB	NM_152764.3		c.1217C>A	p.Thr406Lys	missense splice_region	Exon 12 of 13	NP_689977.2	Q8N635-1
	FAHD1	NM_001018104.3		c.*9-6G>T		splice_region intron	N/A	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.1217C>A	p.Thr406Lys	missense splice_region	Exon 12 of 14	ENSP00000314484.3	Q8N635-2
	FAHD1	ENST00000382668.8	TSL:1	c.628-6G>T		splice_region intron	N/A	ENSP00000372114.5	Q6P587-2
	MEIOB	ENST00000397344.7	TSL:5	c.1217C>A	p.Thr406Lys	missense splice_region	Exon 12 of 13	ENSP00000380504.3	Q8N635-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1434014 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 711596

African (AFR) AF: 0.00 AC: 0 AN: 32144

American (AMR) AF: 0.00 AC: 0 AN: 38780

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25092

East Asian (EAS) AF: 0.00 AC: 0 AN: 38716

South Asian (SAS) AF: 0.00 AC: 0 AN: 81396

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53122

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5664

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1099906

Other (OTH) AF: 0.0000169 AC: 1 AN: 59194

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.046	T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		5.1
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.19
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.19	T
Polyphen		1.0	D
Vest4		0.70
MutPred		0.49		Gain of methylation at T406 (P = 0.0043)
MVP		0.23
ClinPred		0.93	D
GERP RS		6.0
Varity_R		0.43
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.96
dbscSNV1_RF	Pathogenic	0.76
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: rs377366231; hg19: chr16-1889257;