rs367678592

chr6-51748470-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_138694.4(PKHD1):c.9146A>G(p.His3049Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,461,700 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.95

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 4 ACMG points.

• PM1: In a repeat PbH1 8 (size 22) in uniprot entity PKHD1_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_138694.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.9146A>G	p.His3049Arg	missense_variant	58/67	ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.9146A>G	p.His3049Arg	missense_variant	58/67	1	NM_138694.4	P2
PKHD1	ENST00000340994.4	c.9146A>G	p.His3049Arg	missense_variant	58/61	5		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 251028 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135654

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461700 Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10 AN XY: 727146

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: 0.0000162

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 19, 2023

The c.9146A>G (p.H3049R) alteration is located in exon 58 (coding exon 57) of the PKHD1 gene. This alteration results from an A to G substitution at nucleotide position 9146, causing the histidine (H) at amino acid position 3049 to be replaced by an arginine (R). Based on data from gnomAD, the G allele has an overall frequency of 0.001% (3/251028) total alleles studied. The highest observed frequency was 0.003% (3/113480) of European (non-Finnish) alleles. This variant has been reported in trans with a second PKHD1 variant in multiple individuals diagnosed with autosomal recessive polycystic kidney disease (Gunay-Aygun, 2010). This amino acid position is well conserved in available mammalian species. This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Polycystic kidney disease Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKHD1 p.His3049Arg variant was identified in 4 of 166 proband chromosomes (frequency: 0.024) from individuals or families with ARPKD and was not identified in 400 control chromosomes from healthy individuals (Gunay-Aygun 2010, Tong 2016). The variant was also identified in dbSNP (ID: rs367678592) as "With Uncertain significance allele", in ClinVar (classified as uncertain significance by Ambry Genetics), LOVD 3.0, and in RWTH AAachen University ARPKD database (possibly pathogenic). The variant was identified in control databases in 4 of 245786 chromosomes at a frequency of 0.000016 (Genome Aggregation Database Feb 27, 2017). The variant was observed in European population in 4 of 111412 chromosomes (freq: 0.000036), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.His3049 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. -

Autosomal recessive polycystic kidney disease Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 11, 2023

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PKHD1 protein function. ClinVar contains an entry for this variant (Variation ID: 522152). This missense change has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 19914852, 20413436, 31395954). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs367678592, gnomAD 0.004%). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 3049 of the PKHD1 protein (p.His3049Arg). -

Polycystic kidney disease 4 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 31, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.40	T;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.79	T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.56	D;D
MetaSVM	Benign	-0.32	T
MutationAssessor	Uncertain	2.7	M;M
MutationTaster	Benign	0.87	N;N
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Uncertain	0.59
Sift	Benign	0.098	T;T
Sift4G	Benign	0.13	T;T
Polyphen		0.99	D;P
Vest4		0.53
MVP		0.97
MPC		0.41
ClinPred		0.71	D
GERP RS		4.7
Varity_R		0.20
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs367678592; hg19: chr6-51613268; COSMIC: COSV61870095;