16-70828385-A-C

Variant names:

• chr16-70828385-A-C
• NM_001270974.2:c.14157T>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001270974.2(HYDIN):​c.14157T>G​(p.Tyr4719*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000020 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HYDIN NM_001270974.2 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.18
• Publications: 0 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-70828385-A-C is Pathogenic according to our data. Variant chr16-70828385-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3027493.Status of the report is criteria_provided_single_submitter, 1 stars.

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.14157T>G	p.Tyr4719*	stop_gained	Exon 82 of 86	NP_001257903.1	Q4G0P3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HYDIN	ENST00000393567.7	TSL:5 MANE Select	c.14157T>G	p.Tyr4719*	stop_gained	Exon 82 of 86	ENSP00000377197.2	Q4G0P3-1
	HYDIN	ENST00000378856.8	TSL:1	n.*2913T>G		non_coding_transcript_exon	Exon 17 of 22	ENSP00000463350.1	J3QL30
	HYDIN	ENST00000378856.8	TSL:1	n.*2913T>G		3_prime_UTR	Exon 17 of 22	ENSP00000463350.1	J3QL30

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000195 AC: 2 AN: 1025022 Hom.: 0 Cov.: 13 AF XY: 0.00000190 AC XY: 1 AN XY: 525364

African (AFR) AF: 0.00 AC: 0 AN: 23068

American (AMR) AF: 0.00 AC: 0 AN: 28000

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21514

East Asian (EAS) AF: 0.00 AC: 0 AN: 36340

South Asian (SAS) AF: 0.00 AC: 0 AN: 68418

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50762

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4670

European-Non Finnish (NFE) AF: 0.00000268 AC: 2 AN: 746620

Other (OTH) AF: 0.00 AC: 0 AN: 45630

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Primary ciliary dyskinesia 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	36
DANN	Benign	0.93
Eigen	Benign	-0.056
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.46	N
PhyloP100		1.2
Vest4		0.39
GERP RS		0.40
Mutation Taster		=90/110	disease causing (fs/PTC)

Splicing

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

Other links and lift over

hg19: chr16-70862288;