rs62073553

Positions:

• chr17-78507478-C-A
• chr17-78507478-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_173628.4(DNAH17):​c.4564G>T​(p.Asp1522Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.136 in 1,612,306 control chromosomes in the GnomAD database, including 15,983 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1228 hom., cov: 33)
  • Exomes 𝑓: 0.14 (14755 hom.)
• Consequence: DNAH17 NM_173628.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.787

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024757385).
• BP6: Variant 17-78507478-C-A is Benign according to our data. Variant chr17-78507478-C-A is described in ClinVar as [Benign]. Clinvar id is 402689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.153 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH17	NM_173628.4	c.4564G>T	p.Asp1522Tyr	missense_variant	28/81	ENST00000389840.7	NP_775899.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH17	ENST00000389840.7	c.4564G>T	p.Asp1522Tyr	missense_variant	28/81	5	NM_173628.4	ENSP00000374490.6
DNAH17	ENST00000587177.1	n.616G>T		non_coding_transcript_exon_variant	2/7	5

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16936 AN: 152166 Hom.: 1230 Cov.: 33

Gnomad AFR AF: 0.0293

Gnomad AMI AF: 0.0976

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.162

Gnomad EAS AF: 0.0653

Gnomad SAS AF: 0.0871

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.129

GnomAD3 exomes AF: 0.132 AC: 32907 AN: 248942 Hom.: 2411 AF XY: 0.133 AC XY: 17971 AN XY: 135078

Gnomad AFR exome AF: 0.0271

Gnomad AMR exome AF: 0.164

Gnomad ASJ exome AF: 0.167

Gnomad EAS exome AF: 0.0672

Gnomad SAS exome AF: 0.0902

Gnomad FIN exome AF: 0.125

Gnomad NFE exome AF: 0.156

Gnomad OTH exome AF: 0.148

GnomAD4 exome AF: 0.139 AC: 202342 AN: 1460022 Hom.: 14755 Cov.: 64 AF XY: 0.138 AC XY: 100381 AN XY: 725940

Gnomad4 AFR exome AF: 0.0247

Gnomad4 AMR exome AF: 0.163

Gnomad4 ASJ exome AF: 0.166

Gnomad4 EAS exome AF: 0.0579

Gnomad4 SAS exome AF: 0.0911

Gnomad4 FIN exome AF: 0.127

Gnomad4 NFE exome AF: 0.148

Gnomad4 OTH exome AF: 0.132

GnomAD4 genome AF: 0.111 AC: 16935 AN: 152284 Hom.: 1228 Cov.: 33 AF XY: 0.109 AC XY: 8134 AN XY: 74460

Gnomad4 AFR AF: 0.0293

Gnomad4 AMR AF: 0.136

Gnomad4 ASJ AF: 0.162

Gnomad4 EAS AF: 0.0655

Gnomad4 SAS AF: 0.0871

Gnomad4 FIN AF: 0.127

Gnomad4 NFE AF: 0.155

Gnomad4 OTH AF: 0.127

Alfa AF: 0.144 Hom.: 2625

Bravo AF: 0.109

TwinsUK AF: 0.147 AC: 546

ALSPAC AF: 0.145 AC: 560

ESP6500AA AF: 0.0258 AC: 108

ESP6500EA AF: 0.148 AC: 1256

ExAC AF: 0.130 AC: 15686

Asia WGS AF: 0.0710 AC: 247 AN: 3478

EpiCase AF: 0.166

EpiControl AF: 0.158

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

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

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 29, 2019

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.22
DANN	Benign	0.53
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.80	T;T
MetaRNN	Benign	0.0025	T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.25	T
REVEL	Benign	0.031
Vest4		0.35
ClinPred		0.00072	T
GERP RS		-3.3
Varity_R		0.050
gMVP		0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs62073553; hg19: chr17-76503560; COSMIC: COSV67751003; COSMIC: COSV67751003;