16-70809809-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_001270974.2(HYDIN):c.14857C>T(p.Arg4953Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00398 in 1,613,950 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (41 hom.)
• Consequence: HYDIN NM_001270974.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 7.47

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 -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, HYDIN
• BP4: Computational evidence support a benign effect (MetaRNN=0.009678125).
• BP6: Variant 16-70809809-G-A is Benign according to our data. Variant chr16-70809809-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 445775.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1, Benign=1}. Variant chr16-70809809-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00266 (405/152316) while in subpopulation SAS AF= 0.0166 (80/4816). AF 95% confidence interval is 0.0137. There are 2 homozygotes in gnomad4. There are 207 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HYDIN	NM_001270974.2	c.14857C>T	p.Arg4953Trp	missense_variant	85/86	ENST00000393567.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HYDIN	ENST00000393567.7	c.14857C>T	p.Arg4953Trp	missense_variant	85/86	5	NM_001270974.2	P1
HYDIN	ENST00000378856.8	c.*3737C>T		3_prime_UTR_variant, NMD_transcript_variant	21/22	1

Frequencies

GnomAD3 genomes AF: 0.00267 AC: 406 AN: 152198 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00500

Gnomad SAS AF: 0.0168

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00320

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00426 AC: 1063 AN: 249564 Hom.: 12 AF XY: 0.00498 AC XY: 674 AN XY: 135396

Gnomad AFR exome AF: 0.000904

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.00451

Gnomad SAS exome AF: 0.0147

Gnomad FIN exome AF: 0.000464

Gnomad NFE exome AF: 0.00361

Gnomad OTH exome AF: 0.00363

GnomAD4 exome AF: 0.00412 AC: 6020 AN: 1461634 Hom.: 41 Cov.: 31 AF XY: 0.00450 AC XY: 3273 AN XY: 727116

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.00186

Gnomad4 ASJ exome AF: 0.00233

Gnomad4 EAS exome AF: 0.00275

Gnomad4 SAS exome AF: 0.0153

Gnomad4 FIN exome AF: 0.000543

Gnomad4 NFE exome AF: 0.00364

Gnomad4 OTH exome AF: 0.00489

GnomAD4 genome AF: 0.00266 AC: 405 AN: 152316 Hom.: 2 Cov.: 32 AF XY: 0.00278 AC XY: 207 AN XY: 74468

Gnomad4 AFR AF: 0.000698

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00501

Gnomad4 SAS AF: 0.0166

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00320

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00350 Hom.: 4

Bravo AF: 0.00258

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000511 AC: 2

ESP6500EA AF: 0.00326 AC: 27

ExAC AF: 0.00474 AC: 573

Asia WGS AF: 0.0130 AC: 46 AN: 3478

EpiCase AF: 0.00349

EpiControl AF: 0.00379

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 30, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	HYDIN: BP4, BS1, BS2 -

Primary ciliary dyskinesia 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Oct 03, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.16
Cadd	Uncertain	26
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.41	T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.96	D
MetaRNN	Benign	0.0097	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0010	D
Vest4		0.68
MVP		0.38
ClinPred		0.058	T
GERP RS		5.9
Varity_R		0.38
gMVP		0.36

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs79607350; hg19: chr16-70843712;