rs75270082

Positions:

• chr16-71186852-A-G

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.44T>C​(p.Met15Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0515 in 1,612,828 control chromosomes in the GnomAD database, including 2,516 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (175 hom., cov: 32)
  • Exomes 𝑓: 0.053 (2341 hom.)
• Consequence: HYDIN NM_001270974.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.158

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=0.0019213855).
• BP6: Variant 16-71186852-A-G is Benign according to our data. Variant chr16-71186852-A-G is described in ClinVar as [Benign]. Clinvar id is 402958.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-71186852-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0577 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HYDIN	NM_001270974.2	c.44T>C	p.Met15Thr	missense_variant	2/86	ENST00000393567.7
HYDIN	NM_017558.5	c.44T>C	p.Met15Thr	missense_variant	2/20
HYDIN	NM_001198542.1	c.125T>C	p.Met42Thr	missense_variant	2/19
HYDIN	NM_001198543.1	c.95T>C	p.Met32Thr	missense_variant	2/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HYDIN	ENST00000393567.7	c.44T>C	p.Met15Thr	missense_variant	2/86	5	NM_001270974.2	P1

Frequencies

GnomAD3 genomes AF: 0.0387 AC: 5883 AN: 152044 Hom.: 175 Cov.: 32

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.0824

Gnomad AMR AF: 0.0376

Gnomad ASJ AF: 0.0582

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0303

Gnomad FIN AF: 0.0286

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0592

Gnomad OTH AF: 0.0420

GnomAD3 exomes AF: 0.0394 AC: 9884 AN: 250750 Hom.: 290 AF XY: 0.0409 AC XY: 5538 AN XY: 135504

Gnomad AFR exome AF: 0.0120

Gnomad AMR exome AF: 0.0197

Gnomad ASJ exome AF: 0.0593

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0314

Gnomad FIN exome AF: 0.0281

Gnomad NFE exome AF: 0.0578

Gnomad OTH exome AF: 0.0499

GnomAD4 exome AF: 0.0529 AC: 77236 AN: 1460666 Hom.: 2341 Cov.: 30 AF XY: 0.0526 AC XY: 38195 AN XY: 726698

Gnomad4 AFR exome AF: 0.0102

Gnomad4 AMR exome AF: 0.0216

Gnomad4 ASJ exome AF: 0.0604

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0316

Gnomad4 FIN exome AF: 0.0311

Gnomad4 NFE exome AF: 0.0599

Gnomad4 OTH exome AF: 0.0521

GnomAD4 genome AF: 0.0387 AC: 5886 AN: 152162 Hom.: 175 Cov.: 32 AF XY: 0.0373 AC XY: 2774 AN XY: 74394

Gnomad4 AFR AF: 0.0110

Gnomad4 AMR AF: 0.0376

Gnomad4 ASJ AF: 0.0582

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0308

Gnomad4 FIN AF: 0.0286

Gnomad4 NFE AF: 0.0592

Gnomad4 OTH AF: 0.0416

Alfa AF: 0.0531 Hom.: 386

Bravo AF: 0.0378

TwinsUK AF: 0.0569 AC: 211

ALSPAC AF: 0.0553 AC: 213

ESP6500AA AF: 0.00978 AC: 43

ESP6500EA AF: 0.0601 AC: 517

ExAC AF: 0.0411 AC: 4986

Asia WGS AF: 0.0110 AC: 37 AN: 3478

EpiCase AF: 0.0619

EpiControl AF: 0.0563

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	9.4
DANN	Benign	0.36
DEOGEN2	Benign	0.035	T;.;.;.;T;.;.
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.034	N
MetaRNN	Benign	0.0019	T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.1	L;L;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.24	N;N;N;N;N;.;.
REVEL	Benign	0.081
Sift	Benign	0.39	T;T;T;T;T;.;.
Sift4G	Benign	1.0	.;T;T;T;T;.;.
Polyphen		0.0020	.;B;.;.;B;.;.
Vest4		0.37
ClinPred		0.0053	T
GERP RS		-0.019
Varity_R		0.033
gMVP		0.69

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: rs75270082; hg19: chr16-71220755;