chr14-60483718-CTA-C

Variant names:

• chr14-60483718-CTA-C
• rs1406759691
• NM_174978.3:c.204_205delTA

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_174978.3(C14orf39):​c.204_205delTA​(p.His68GlnfsTer2) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000138 in 1,445,038 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: C14orf39 NM_174978.3 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:4
• Conservation: PhyloP100: 3.72
• Publications: 1 publications found

Genes affected

C14orf39 (HGNC:19849): (chromosome 14 open reading frame 39) Predicted to be involved in gamete generation and meiosis I. Predicted to be located in chromosome. Predicted to be active in central element. Implicated in primary ovarian insufficiency 18 and spermatogenic failure 52. [provided by Alliance of Genome Resources, Apr 2022]

C14orf39 Gene-Disease associations (from GenCC):

• premature ovarian failure 18

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• spermatogenic failure 52

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 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 14-60483718-CTA-C is Pathogenic according to our data. Variant chr14-60483718-CTA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 992822.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_174978.3. 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
	C14orf39	NM_174978.3	MANE Select	c.204_205delTA	p.His68GlnfsTer2	frameshift	Exon 4 of 18	NP_777638.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C14orf39	ENST00000321731.8	TSL:1 MANE Select	c.204_205delTA	p.His68GlnfsTer2	frameshift	Exon 4 of 18	ENSP00000324920.3	Q8N1H7
	C14orf39	ENST00000557138.5	TSL:1	n.106+1161_106+1162delTA		intron	N/A	ENSP00000450476.1	G3V257
	C14orf39	ENST00000917634.1		c.204_205delTA	p.His68GlnfsTer2	frameshift	Exon 4 of 18	ENSP00000587693.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000414 AC: 1 AN: 241674 AF XY: 0.00000765

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000903

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1445038 Hom.: 0 AF XY: 0.00000278 AC XY: 2 AN XY: 719214

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

African (AFR) AF: 0.00 AC: 0 AN: 32780

American (AMR) AF: 0.00 AC: 0 AN: 42934

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25874

East Asian (EAS) AF: 0.00 AC: 0 AN: 39098

South Asian (SAS) AF: 0.00 AC: 0 AN: 83806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53108

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1101882

Other (OTH) AF: 0.00 AC: 0 AN: 59836

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Azoospermia (1)
1	-	-	Non-obstructive azoospermia (1)
1	-	-	Premature ovarian failure 18 (1)
1	-	-	Spermatogenic failure 52 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.7
Mutation Taster		=43/157	disease causing (ClinVar)

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: rs1406759691; hg19: chr14-60950436;