17-78529483-A-G

Variant names:

• chr17-78529483-A-G
• rs4273108
• NM_173628.4:c.3496T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_173628.4(DNAH17):​c.3496T>C​(p.Leu1166Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.609 in 1,613,440 control chromosomes in the GnomAD database, including 300,753 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (28713 hom., cov: 30)
  • Exomes 𝑓: 0.61 (272040 hom.)
• Consequence: DNAH17 NM_173628.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.00900
• Publications: 16 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 17-78529483-A-G is Benign according to our data. Variant chr17-78529483-A-G is described in ClinVar as Benign. ClinVar VariationId is 402694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.009 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.63 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH17	NM_173628.4	c.3496T>C	p.Leu1166Leu	synonymous_variant	Exon 22 of 81	ENST00000389840.7	NP_775899.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH17	ENST00000389840.7	c.3496T>C	p.Leu1166Leu	synonymous_variant	Exon 22 of 81	5	NM_173628.4	ENSP00000374490.6

Frequencies

GnomAD3 genomes AF: 0.613 AC: 92970 AN: 151750 Hom.: 28689 Cov.: 30

Gnomad AFR AF: 0.636

Gnomad AMI AF: 0.676

Gnomad AMR AF: 0.590

Gnomad ASJ AF: 0.575

Gnomad EAS AF: 0.602

Gnomad SAS AF: 0.499

Gnomad FIN AF: 0.534

Gnomad MID AF: 0.642

Gnomad NFE AF: 0.624

Gnomad OTH AF: 0.647

GnomAD2 exomes AF: 0.589 AC: 146709 AN: 249090 AF XY: 0.588

Gnomad AFR exome AF: 0.634

Gnomad AMR exome AF: 0.551

Gnomad ASJ exome AF: 0.593

Gnomad EAS exome AF: 0.614

Gnomad FIN exome AF: 0.540

Gnomad NFE exome AF: 0.624

Gnomad OTH exome AF: 0.603

GnomAD4 exome AF: 0.609 AC: 889810 AN: 1461572 Hom.: 272040 Cov.: 54 AF XY: 0.606 AC XY: 440456 AN XY: 727066

African (AFR) AF: 0.635 AC: 21247 AN: 33480

American (AMR) AF: 0.557 AC: 24906 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.589 AC: 15404 AN: 26132

East Asian (EAS) AF: 0.588 AC: 23330 AN: 39698

South Asian (SAS) AF: 0.504 AC: 43439 AN: 86252

European-Finnish (FIN) AF: 0.541 AC: 28910 AN: 53392

Middle Eastern (MID) AF: 0.642 AC: 3702 AN: 5768

European-Non Finnish (NFE) AF: 0.622 AC: 691955 AN: 1111762

Other (OTH) AF: 0.612 AC: 36917 AN: 60368

GnomAD4 genome AF: 0.613 AC: 93041 AN: 151868 Hom.: 28713 Cov.: 30 AF XY: 0.606 AC XY: 44985 AN XY: 74238

African (AFR) AF: 0.636 AC: 26345 AN: 41394

American (AMR) AF: 0.591 AC: 9014 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.575 AC: 1995 AN: 3472

East Asian (EAS) AF: 0.602 AC: 3099 AN: 5146

South Asian (SAS) AF: 0.498 AC: 2392 AN: 4802

European-Finnish (FIN) AF: 0.534 AC: 5646 AN: 10572

Middle Eastern (MID) AF: 0.633 AC: 186 AN: 294

European-Non Finnish (NFE) AF: 0.624 AC: 42392 AN: 67906

Other (OTH) AF: 0.642 AC: 1357 AN: 2114

Alfa AF: 0.626 Hom.: 85939

Bravo AF: 0.622

Asia WGS AF: 0.540 AC: 1878 AN: 3478

EpiCase AF: 0.636

EpiControl AF: 0.643

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

DNAH17-related disorder Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.090
DANN	Benign	0.53
PhyloP100		-0.0090
Mutation Taster		=100/0	polymorphism (auto)

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: rs4273108; hg19: chr17-76525565; COSMIC: COSV67750636; COSMIC: COSV67750636;