rs78763837

Positions:

• chr16-70981426-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001270974.2(HYDIN):​c.4475C>A​(p.Pro1492His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.357 in 1,612,908 control chromosomes in the GnomAD database, including 108,409 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12231 hom., cov: 29)
  • Exomes 𝑓: 0.35 (96178 hom.)
• Consequence: HYDIN NM_001270974.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 9.30

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]

ACMG classification

Verdict is Benign. Variant got -19 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=3.117323E-4).
• BP6: Variant 16-70981426-G-T is Benign according to our data. Variant chr16-70981426-G-T is described in ClinVar as [Benign]. Clinvar id is 402956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.555 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HYDIN	NM_001270974.2	c.4475C>A	p.Pro1492His	missense_variant	29/86	ENST00000393567.7	NP_001257903.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HYDIN	ENST00000393567.7	c.4475C>A	p.Pro1492His	missense_variant	29/86	5	NM_001270974.2	ENSP00000377197	P1

Frequencies

GnomAD3 genomes AF: 0.392 AC: 59384 AN: 151604 Hom.: 12210 Cov.: 29

Gnomad AFR AF: 0.446

Gnomad AMI AF: 0.260

Gnomad AMR AF: 0.517

Gnomad ASJ AF: 0.400

Gnomad EAS AF: 0.572

Gnomad SAS AF: 0.477

Gnomad FIN AF: 0.283

Gnomad MID AF: 0.372

Gnomad NFE AF: 0.329

Gnomad OTH AF: 0.384

GnomAD3 exomes AF: 0.415 AC: 102952 AN: 248302 Hom.: 23178 AF XY: 0.408 AC XY: 54928 AN XY: 134702

Gnomad AFR exome AF: 0.443

Gnomad AMR exome AF: 0.635

Gnomad ASJ exome AF: 0.402

Gnomad EAS exome AF: 0.567

Gnomad SAS exome AF: 0.477

Gnomad FIN exome AF: 0.286

Gnomad NFE exome AF: 0.329

Gnomad OTH exome AF: 0.396

GnomAD4 exome AF: 0.354 AC: 516692 AN: 1461182 Hom.: 96178 Cov.: 37 AF XY: 0.356 AC XY: 259088 AN XY: 726860

Gnomad4 AFR exome AF: 0.448

Gnomad4 AMR exome AF: 0.621

Gnomad4 ASJ exome AF: 0.405

Gnomad4 EAS exome AF: 0.570

Gnomad4 SAS exome AF: 0.473

Gnomad4 FIN exome AF: 0.287

Gnomad4 NFE exome AF: 0.324

Gnomad4 OTH exome AF: 0.372

GnomAD4 genome AF: 0.392 AC: 59441 AN: 151726 Hom.: 12231 Cov.: 29 AF XY: 0.396 AC XY: 29333 AN XY: 74150

Gnomad4 AFR AF: 0.446

Gnomad4 AMR AF: 0.518

Gnomad4 ASJ AF: 0.400

Gnomad4 EAS AF: 0.573

Gnomad4 SAS AF: 0.476

Gnomad4 FIN AF: 0.283

Gnomad4 NFE AF: 0.329

Gnomad4 OTH AF: 0.383

Alfa AF: 0.353 Hom.: 8067

Bravo AF: 0.414

ExAC AF: 0.407 AC: 49212

Asia WGS AF: 0.512 AC: 1781 AN: 3476

EpiCase AF: 0.344

EpiControl AF: 0.338

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Primary ciliary dyskinesia 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.00031	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	0.00035	P;P
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-7.1	D
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D
Vest4		0.34
ClinPred		0.032	T
GERP RS		4.3
Varity_R		0.76
gMVP		0.70

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs78763837; hg19: chr16-71015329; COSMIC: COSV66829426; COSMIC: COSV66829426;