6-51616037-T-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_138694.4(PKHD1):c.*3044A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0175 in 152,210 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.018 (38 hom., cov: 31)
  • Failed GnomAD Quality Control
• Consequence: PKHD1 NM_138694.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.419

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 6-51616037-T-A is Benign according to our data. Variant chr6-51616037-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 908895.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0175 (2665/152210) while in subpopulation NFE AF= 0.0267 (1818/68012). AF 95% confidence interval is 0.0257. There are 38 homozygotes in gnomad4. There are 1254 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 36 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.*3044A>T		3_prime_UTR_variant	67/67	ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.*3044A>T		3_prime_UTR_variant	67/67	1	NM_138694.4	P2
	ENST00000589278.6	n.811-6323T>A		intron_variant, non_coding_transcript_variant		5
	ENST00000454361.1	n.81-6318T>A		intron_variant, non_coding_transcript_variant		3
	ENST00000650088.1	n.221+5605T>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0175 AC: 2663 AN: 152092 Hom.: 36 Cov.: 31

Gnomad AFR AF: 0.00519

Gnomad AMI AF: 0.0680

Gnomad AMR AF: 0.0151

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0199

Gnomad FIN AF: 0.0106

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0267

Gnomad OTH AF: 0.0182

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.0175 AC: 2665 AN: 152210 Hom.: 38 Cov.: 31 AF XY: 0.0169 AC XY: 1254 AN XY: 74420

Gnomad4 AFR AF: 0.00518

Gnomad4 AMR AF: 0.0153

Gnomad4 ASJ AF: 0.0245

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0195

Gnomad4 FIN AF: 0.0106

Gnomad4 NFE AF: 0.0267

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.0224 Hom.: 7

Bravo AF: 0.0173

Asia WGS AF: 0.00953 AC: 33 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive polycystic kidney disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	1.9
Dann	Benign	0.66

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

Publications

LitVar

Other links and lift over

dbSNP: rs41273712; hg19: chr6-51480835;