rs745776920
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The NM_001017361.3(KHDC3L):c.334C>T(p.Gln112Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,614,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000010 ( 0 hom. )
Consequence
KHDC3L
NM_001017361.3 stop_gained
NM_001017361.3 stop_gained
Scores
1
1
5
Clinical Significance
Conservation
PhyloP100: 0.313
Genes affected
KHDC3L (HGNC:33699): (KH domain containing 3 like, subcortical maternal complex member) The protein encoded by this gene belongs to the KHDC1 family, members of which contain an atypical KH domain that may not bind RNA like canonical KH domains. This gene is specifically expressed in the oocytes, and recent studies suggest that it may function as a regulator of genomic imprinting in the oocyte. Mutations in this gene are associated with recurrent biparental complete hydatidiform mole. [provided by RefSeq, Dec 2011]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.489 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 6-73363259-C-T is Pathogenic according to our data. Variant chr6-73363259-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 208592.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-73363259-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KHDC3L | NM_001017361.3 | c.334C>T | p.Gln112Ter | stop_gained | 2/3 | ENST00000370367.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KHDC3L | ENST00000370367.4 | c.334C>T | p.Gln112Ter | stop_gained | 2/3 | 1 | NM_001017361.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152194Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
1
AN:
152194
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251230Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135880
GnomAD3 exomes
AF:
AC:
4
AN:
251230
Hom.:
AF XY:
AC XY:
0
AN XY:
135880
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461858Hom.: 0 Cov.: 33 AF XY: 0.0000110 AC XY: 8AN XY: 727238
GnomAD4 exome
AF:
AC:
15
AN:
1461858
Hom.:
Cov.:
33
AF XY:
AC XY:
8
AN XY:
727238
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152194Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74356
GnomAD4 genome
?
AF:
AC:
1
AN:
152194
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
74356
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ExAC
?
AF:
AC:
2
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hydatidiform mole, recurrent, 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 16, 2014 | The p.Gln112X variant in KHDC3L has not been previously reported in individuals with disease or in large population studies. This nonsense variant leads to a premature termination codon at position 112, which is predicted to remove roughly half of the protein and therefore likely to result in a null or loss of function effect. Biallelic null variants (variants in both copies of the gene) have been shown to cause hydatidiform mole (Parry 2011, Reddy 2013). In summary, although additional studies are required to confirm a null effect, the p.Gln112X variant in KHDC3L is likely pathogenic for hydatidiform mole in an autosomal recessive manner. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
MutationTaster
Benign
D
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at