16-71186765-C-T

Position:

chr16-71186765-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_001270974.2(HYDIN):c.131G>A(p.Arg44Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00433 in 1,610,892 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0036 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0044 ( 25 hom. )

Consequence

HYDIN
NM_001270974.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: -1.69

Variant links:

Genes affected

HYDIN (HGNC:19368): (HYDIN axonemal central pair apparatus protein) This gene encodes a protein that may be involved in cilia motility. Mutations in this gene cause of autosomal recessive primary ciliary dyskinesia-5, a disorder characterized by the accumulation of cerebrospinal fluid within the ventricles of the brain. A duplicate copy of this gene has been found in humans on chromosome 1. [provided by RefSeq, Jan 2013]

HYDIN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HYDIN. . Gene score misZ 0.81019 (greater than the threshold 3.09). Trascript score misZ 4.6175 (greater than threshold 3.09). GenCC has associacion of gene with primary ciliary dyskinesia 5, primary ciliary dyskinesia.

BP4

Computational evidence support a benign effect (MetaRNN=0.002897948).

BP6

Variant 16-71186765-C-T is Benign according to our data. Variant chr16-71186765-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 547951.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}. Variant chr16-71186765-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00359 (547/152202) while in subpopulation NFE AF= 0.00494 (336/67990). AF 95% confidence interval is 0.00451. There are 3 homozygotes in gnomad4. There are 251 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HYDIN	NM_001270974.2 linkuse as main transcript	c.131G>A	p.Arg44Gln	missense_variant	2/86	ENST00000393567.7	NP_001257903.1	Q4G0P3-1
HYDIN	NM_017558.5 linkuse as main transcript	c.131G>A	p.Arg44Gln	missense_variant	2/20		NP_060028.2	Q4G0P3-5
HYDIN	NM_001198542.1 linkuse as main transcript	c.212G>A	p.Arg71Gln	missense_variant	2/19		NP_001185471.1	Q4G0P3-8
HYDIN	NM_001198543.1 linkuse as main transcript	c.182G>A	p.Arg61Gln	missense_variant	2/19		NP_001185472.1	Q4G0P3-10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HYDIN	ENST00000393567.7 linkuse as main transcript	c.131G>A	p.Arg44Gln	missense_variant	2/86	5	NM_001270974.2	ENSP00000377197.2		Q4G0P3-1

Frequencies

GnomAD3 genomes

AF:

0.00360

AC:

547

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000869

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.0245

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00349

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00494

Gnomad OTH

AF:

0.00334

GnomAD3 exomes

AF:

0.00349

AC:

867

AN:

248642

Hom.:

AF XY:

0.00336

AC XY:

451

AN XY:

134398

show subpopulations

Gnomad AFR exome

AF:

0.000989

Gnomad AMR exome

AF:

0.00158

Gnomad ASJ exome

AF:

0.0205

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00427

Gnomad NFE exome

AF:

0.00428

Gnomad OTH exome

AF:

0.00347

GnomAD4 exome

AF:

0.00441

AC:

6429

AN:

1458690

Hom.:

Cov.:

AF XY:

0.00424

AC XY:

3077

AN XY:

725698

show subpopulations

Gnomad4 AFR exome

AF:

0.000780

Gnomad4 AMR exome

AF:

0.00149

Gnomad4 ASJ exome

AF:

0.0215

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00399

Gnomad4 NFE exome

AF:

0.00476

Gnomad4 OTH exome

AF:

0.00466

GnomAD4 genome

AF:

0.00359

AC:

547

AN:

152202

Hom.:

Cov.:

AF XY:

0.00337

AC XY:

251

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.000866

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.0245

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00349

Gnomad4 NFE

AF:

0.00494

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00532

Hom.:

Bravo

AF:

0.00365

TwinsUK

AF:

0.00674

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.000682

AC:

ESP6500EA

AF:

0.00430

AC:

ExAC

AF:

0.00306

AC:

371

EpiCase

AF:

0.00366

EpiControl

AF:

0.00440

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	HYDIN: BP4, BS2 -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Primary ciliary dyskinesia 5

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 12, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Apr 23, 2020	- -

HYDIN-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 11, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.58

CADD

Benign

6.5

DANN

Benign

0.66

DEOGEN2

Benign

0.023

T;.;.;.;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0058

M_CAP

Benign

0.0025

MetaRNN

Benign

0.0029

T;T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.41

N;N;.;.;.

PrimateAI

Benign

0.20

PROVEAN

Benign

-0.070

N;N;N;N;N

REVEL

Benign

0.11

Sift

Benign

0.61

T;T;T;T;T

Sift4G

Benign

0.15

.;T;T;T;T

Polyphen

0.0020, 0.0030

.;B;.;.;B

Vest4

0.10

MVP

0.11

ClinPred

0.00096

GERP RS

-7.8

Varity_R

0.025

gMVP

0.20

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