chr17-78427016-G-T

Variant names:

• chr17-78427016-G-T
• rs2271613
• NM_173628.4:c.12681C>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_173628.4(DNAH17):​c.12681C>A​(p.Tyr4227*) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Y4227Y) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DNAH17 NM_173628.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.423
• Publications: 0 publications found

Genes affected

DNAH17 (HGNC:2946): (dynein axonemal heavy chain 17) Dyneins are microtubule-associated motor protein complexes composed of several heavy, light, and intermediate chains. DNAH17 is a heavy chain associated with axonemal dynein (Milisav and Affara, 1998 [PubMed 9545504]).[supplied by OMIM, Mar 2008]

DNAH17 Gene-Disease associations (from GenCC):

• spermatogenic failure 39

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• non-syndromic male infertility due to sperm motility disorder

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173628.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH17	NM_173628.4	MANE Select	c.12681C>A	p.Tyr4227*	stop_gained	Exon 78 of 81	NP_775899.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH17	ENST00000389840.7	TSL:5 MANE Select	c.12681C>A	p.Tyr4227*	stop_gained	Exon 78 of 81	ENSP00000374490.6
	DNAH17	ENST00000586052.5	TSL:5	n.5842C>A		non_coding_transcript_exon	Exon 32 of 35
	DNAH17	ENST00000586850.1	TSL:3	n.213C>A		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000481 AC: 7 AN: 1455928 Hom.: 0 Cov.: 59 AF XY: 0.00000415 AC XY: 3 AN XY: 723630

African (AFR) AF: 0.00 AC: 0 AN: 33388

American (AMR) AF: 0.00 AC: 0 AN: 43828

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25930

East Asian (EAS) AF: 0.00 AC: 0 AN: 39564

South Asian (SAS) AF: 0.00 AC: 0 AN: 85104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52956

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000631 AC: 7 AN: 1109226

Other (OTH) AF: 0.00 AC: 0 AN: 60168

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	39
DANN	Uncertain	0.98
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.40	N
PhyloP100		-0.42
Vest4		0.29
GERP RS		-4.8

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: rs2271613; hg19: chr17-76423097;