NM_138694.4:c.2948G>A
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_138694.4(PKHD1):c.2948G>A(p.Cys983Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,752 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 Uncertain significance (★).
Frequency
Consequence
NM_138694.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PKHD1 | ENST00000371117.8 | c.2948G>A | p.Cys983Tyr | missense_variant | Exon 27 of 67 | 1 | NM_138694.4 | ENSP00000360158.3 | ||
PKHD1 | ENST00000340994.4 | c.2948G>A | p.Cys983Tyr | missense_variant | Exon 27 of 61 | 5 | ENSP00000341097.4 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461752Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727178
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Polycystic kidney disease Uncertain:1
The PKHD1 p.Cys983Tyr variant was not identified in the literature, nor was it identified in the dbSNP, NHLBI Exome Sequencing Project, Exome Aggregation Consortium (14 March 2016), Clinvitae, the ClinVar, GeneInsight COGR, MutDB, RWTH AAachen University ARPKD and PKHD1-LOVD databases. The p.Cys983 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Tyrosine variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Polycystic kidney disease 4 Uncertain:1
A heterozygous missense variant was identified NM_138694.3(PKHD1):c.2948G>A in exon 27 of 67 of the PKHD1 gene. This substitution is predicted to create a major amino acid change from cysteine to tyrosine at position 983 of the protein, NP_619639.3(PKHD1):p.(Cys983Tyr). The cysteine at this position has very high conservation (100 vertebrates, UCSC), and is located within the IPT/TIG 4 functional domain. In silico software predicts this variant to be disease causing (Polyphen, SIFT, CADD, Mutation Taster). The variant is not present in the gnomAD population database. The variant has been previously reported as a VUS in a clinical testing setting (ClinVar). Subsequent analysis of parental samples indicated this variant was paternally inherited. Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS) with POTENTIAL CLINICAL RELEVANCE. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at