rs113448164

Variant names:

• chr16-71186765-C-T
• rs113448164
• NM_001270974.2:c.131G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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. 16/22 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: -1.69
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 5

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• 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 VariationId is 547951.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001270974.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HYDIN	NM_001270974.2	MANE Select	c.131G>A	p.Arg44Gln	missense	Exon 2 of 86	NP_001257903.1	Q4G0P3-1
	HYDIN	NM_017558.5		c.131G>A	p.Arg44Gln	missense	Exon 2 of 20	NP_060028.2
	HYDIN	NM_001198542.1		c.212G>A	p.Arg71Gln	missense	Exon 2 of 19	NP_001185471.1	Q4G0P3-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HYDIN	ENST00000393567.7	TSL:5 MANE Select	c.131G>A	p.Arg44Gln	missense	Exon 2 of 86	ENSP00000377197.2	Q4G0P3-1
	HYDIN	ENST00000288168.14	TSL:1	c.182G>A	p.Arg61Gln	missense	Exon 2 of 15	ENSP00000288168.10	F8WD03
	HYDIN	ENST00000539447.5	TSL:1	n.32G>A		non_coding_transcript_exon	Exon 1 of 19	ENSP00000463093.1	J3KTP9

Frequencies

GnomAD3 genomes AF: 0.00360 AC: 547 AN: 152084 Hom.: 3 Cov.: 32

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

GnomAD2 exomes AF: 0.00349 AC: 867 AN: 248642 AF XY: 0.00336

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 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.: 25 Cov.: 30 AF XY: 0.00424 AC XY: 3077 AN XY: 725698

African (AFR) AF: 0.000780 AC: 26 AN: 33348

American (AMR) AF: 0.00149 AC: 66 AN: 44430

Ashkenazi Jewish (ASJ) AF: 0.0215 AC: 560 AN: 26024

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39644

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85752

European-Finnish (FIN) AF: 0.00399 AC: 213 AN: 53348

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5754

European-Non Finnish (NFE) AF: 0.00476 AC: 5280 AN: 1110124

Other (OTH) AF: 0.00466 AC: 281 AN: 60266

GnomAD4 genome AF: 0.00359 AC: 547 AN: 152202 Hom.: 3 Cov.: 32 AF XY: 0.00337 AC XY: 251 AN XY: 74410

African (AFR) AF: 0.000866 AC: 36 AN: 41552

American (AMR) AF: 0.00144 AC: 22 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0245 AC: 85 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00349 AC: 37 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00494 AC: 336 AN: 67990

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00505 Hom.: 9

Bravo AF: 0.00365

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.00430 AC: 37

ExAC AF: 0.00306 AC: 371

EpiCase AF: 0.00366

EpiControl AF: 0.00440

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	1	Primary ciliary dyskinesia 5 (2)
-	-	1	HYDIN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	6.5
DANN	Benign	0.66
DEOGEN2	Benign	0.023	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0058	N
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.41	N
PhyloP100		-1.7
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.11
Sift	Benign	0.61	T
Sift4G	Benign	0.15	T
Polyphen		0.0020	B
Vest4		0.10
MVP		0.11
ClinPred		0.00096	T
GERP RS		-7.8
Varity_R		0.025
gMVP		0.20
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs113448164; hg19: chr16-71220668; COSMIC: COSV55484690; COSMIC: COSV55484690;