NM_138694.4:c.1159_1161delAAT

Variant names:

• chr6-52059999-AATT-A
• rs1554218506
• NM_138694.4:c.1159_1161delAAT

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PM4_Supporting PP5

The NM_138694.4(PKHD1):​c.1159_1161delAAT​(p.Asn387del) variant causes a conservative inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PKHD1 NM_138694.4 conservative_inframe_deletion
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.24
• Publications: 0 publications found

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]

PKHD1 Gene-Disease associations (from GenCC):

• autosomal recessive polycystic kidney disease

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Myriad Women’s Health, Orphanet
• polycystic kidney disease 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Genomics England PanelApp
• Caroli disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_138694.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_138694.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 6-52059999-AATT-A is Pathogenic according to our data. Variant chr6-52059999-AATT-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 434015.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.1159_1161delAAT	p.Asn387del	conservative_inframe_deletion	Exon 15 of 67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.1159_1161delAAT	p.Asn387del	conservative_inframe_deletion	Exon 15 of 67	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4	c.1159_1161delAAT	p.Asn387del	conservative_inframe_deletion	Exon 15 of 61	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Polycystic kidney disease Pathogenic:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKHD1 p.Asn387del variant was identified in 1 of 308 proband chromosomes (frequency: 0.003) from unrelated individuals or families with ARPKD and was not identified in 520 control chromosomes from healthy individuals (Furu 2004, Sharp 2005). Furu et al (2004) identified the variant in an American caucasian individual in which severe perinatal disease led to neonatal death; with the variant co-occurring with another PKHD1 pathogenic mutation (c.5825A>G, p. Asp1942Gly). The variant was identified in RWTH AAachen University ARPKD database (classification pathogenic) and PKHD1-LOVD (unclassified); and was not identified in dbSNP, Clinvitae database, the ClinVar database, GeneInsight COGR database, 1000 Genomes Project, NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium database (March 14, 2016). This variant is an in-frame deletion resulting in the removal of amino acid residue asparagine at codon 387. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.2
Mutation Taster		=31/69	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: rs1554218506; hg19: chr6-51924797;