8-109382539-G-A

Position:

• chr8-109382539-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_177531.6(PKHD1L1):​c.385G>A​(p.Gly129Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 152,068 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: PKHD1L1 NM_177531.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.50

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-109382539-G-A is Pathogenic according to our data. Variant chr8-109382539-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3220942.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKHD1L1	NM_177531.6	c.385G>A	p.Gly129Ser	missense_variant	4/78	ENST00000378402.10	NP_803875.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKHD1L1	ENST00000378402.10	c.385G>A	p.Gly129Ser	missense_variant	4/78	1	NM_177531.6	ENSP00000367655.5

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152068 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152068 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74296

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 124 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.017	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.054	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Uncertain	2.3	M
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.55
Sift	Benign	0.17	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.67
MutPred		0.46		Gain of disorder (P = 0.0961);
MVP		0.29
MPC		0.23
ClinPred		0.96	D
GERP RS		5.1
Varity_R		0.12
gMVP		0.66

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: rs773702657; hg19: chr8-110394768;