rs28937907

chr6-52024819-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_138694.4(PKHD1):c.4991C>T(p.Ser1664Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1664P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.73

Genes affected

PKHD1 (HGNC:9016): (PKHD1 ciliary IPT domain containing fibrocystin/polyductin) The protein encoded by this gene is predicted to have a single transmembrane (TM)-spanning domain and multiple copies of an immunoglobulin-like plexin-transcription-factor domain. Alternative splicing results in two transcript variants encoding different isoforms. Other alternatively spliced transcripts have been described, but the full length sequences have not been determined. Several of these transcripts are predicted to encode truncated products which lack the TM and may be secreted. Mutations in this gene cause autosomal recessive polycystic kidney disease, also known as polycystic kidney and hepatic disease-1. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a domain IPT/TIG 12; atypical (size 84) in uniprot entity PKHD1_HUMAN there are 18 pathogenic changes around while only 5 benign (78%) in NM_138694.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-52024819-G-A is Pathogenic according to our data. Variant chr6-52024819-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 4109.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr6-52024819-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.4991C>T	p.Ser1664Phe	missense_variant	32/67	ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.4991C>T	p.Ser1664Phe	missense_variant	32/67	1	NM_138694.4	P2
PKHD1	ENST00000340994.4	c.4991C>T	p.Ser1664Phe	missense_variant	32/61	5		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461886 Hom.: 0 Cov.: 34 AF XY: 0.00000413 AC XY: 3 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive polycystic kidney disease Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2002

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;.
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.83	T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.7	M;M
MutationTaster	Benign	0.0000056	A;A
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.9	D;N
REVEL	Uncertain	0.41
Sift	Benign	0.032	D;D
Sift4G	Benign	0.16	T;T
Polyphen		0.96	D;D
Vest4		0.36
MutPred		0.47		Loss of disorder (P = 0.0255);Loss of disorder (P = 0.0255);
MVP		0.98
MPC		0.31
ClinPred		0.95	D
GERP RS		3.2
Varity_R		0.12
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.35		Position offset: -5

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

Publications

LitVar

Other links and lift over

dbSNP: rs28937907; hg19: chr6-51889617;