Genetic Variant PKHD1L1:p.His94Gln (chr8-109381488-T-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_177531.6(PKHD1L1):c.282T>A(p.His94Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,428,350 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PKHD1L1
NM_177531.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.20

Variant links:

Genes affected

PKHD1L1 (HGNC:20313): (PKHD1 like 1) Predicted to act upstream of or within sensory perception of sound. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

PKHD1L1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.4125557).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1L1	NM_177531.6 link	c.282T>A	p.His94Gln	missense_variant	Exon 3 of 78	ENST00000378402.10	NP_803875.2	Q86WI1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1L1	ENST00000378402.10 link	c.282T>A	p.His94Gln	missense_variant	Exon 3 of 78	1	NM_177531.6	ENSP00000367655.5		Q86WI1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000964

AC:

AN:

207370

Hom.:

AF XY:

0.00000900

AC XY:

AN XY:

111060

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000130

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000140

AC:

AN:

1428350

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

708076

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000515

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 18, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.282T>A (p.H94Q) alteration is located in exon 3 (coding exon 3) of the PKHD1L1 gene. This alteration results from a T to A substitution at nucleotide position 282, causing the histidine (H) at amino acid position 94 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Uncertain

0.020

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.70

M_CAP

Benign

0.022

MetaRNN

Benign

0.41

MetaSVM

Uncertain

0.21

MutationAssessor

Uncertain

2.6

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.30

Sift

Benign

0.11

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.47

MutPred

0.27

Gain of disorder (P = 0.0849);

MVP

0.39

MPC

0.23

ClinPred

0.82

GERP RS

6.2

Varity_R

0.32

gMVP

0.65

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over