rs61742072

chr17-78437817-G-Achr17-78437817-G-Cchr17-78437817-G-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.11857C>T(p.His3953Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 1,611,708 control chromosomes in the GnomAD database, including 22,566 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H3953R) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.13 (1506 hom., cov: 29)
  • Exomes 𝑓: 0.17 (21060 hom.)
• Consequence: DNAH17 NM_173628.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.63

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015000999).
• BP6: Variant 17-78437817-G-A is Benign according to our data. Variant chr17-78437817-G-A is described in ClinVar as [Benign]. Clinvar id is 402675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH17	NM_173628.4	c.11857C>T	p.His3953Tyr	missense_variant	74/81	ENST00000389840.7
DNAH17	XM_011525416.3	c.11869C>T	p.His3957Tyr	missense_variant	74/81
DNAH17	XM_024451013.2	c.11725C>T	p.His3909Tyr	missense_variant	73/80

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH17	ENST00000389840.7	c.11857C>T	p.His3953Tyr	missense_variant	74/81	5	NM_173628.4	P1
DNAH17	ENST00000586052.5	n.4993C>T		non_coding_transcript_exon_variant	28/35	5
DNAH17	ENST00000590227.5	n.1531C>T		non_coding_transcript_exon_variant	6/13	2
DNAH17	ENST00000591369.5	c.3460C>T	p.His1154Tyr	missense_variant, NMD_transcript_variant	21/28	5

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19476 AN: 152112 Hom.: 1505 Cov.: 29

Gnomad AFR AF: 0.0523

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.199

Gnomad EAS AF: 0.0943

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.147

GnomAD3 exomes AF: 0.142 AC: 35251 AN: 248778 Hom.: 2874 AF XY: 0.149 AC XY: 20134 AN XY: 135106

Gnomad AFR exome AF: 0.0427

Gnomad AMR exome AF: 0.0837

Gnomad ASJ exome AF: 0.197

Gnomad EAS exome AF: 0.0925

Gnomad SAS exome AF: 0.152

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.178

Gnomad OTH exome AF: 0.165

GnomAD4 exome AF: 0.165 AC: 240842 AN: 1459478 Hom.: 21060 Cov.: 35 AF XY: 0.165 AC XY: 119862 AN XY: 725962

Gnomad4 AFR exome AF: 0.0447

Gnomad4 AMR exome AF: 0.0860

Gnomad4 ASJ exome AF: 0.203

Gnomad4 EAS exome AF: 0.0773

Gnomad4 SAS exome AF: 0.154

Gnomad4 FIN exome AF: 0.114

Gnomad4 NFE exome AF: 0.178

Gnomad4 OTH exome AF: 0.156

GnomAD4 genome AF: 0.128 AC: 19476 AN: 152230 Hom.: 1506 Cov.: 29 AF XY: 0.125 AC XY: 9282 AN XY: 74448

Gnomad4 AFR AF: 0.0524

Gnomad4 AMR AF: 0.115

Gnomad4 ASJ AF: 0.199

Gnomad4 EAS AF: 0.0939

Gnomad4 SAS AF: 0.150

Gnomad4 FIN AF: 0.112

Gnomad4 NFE AF: 0.175

Gnomad4 OTH AF: 0.146

Alfa AF: 0.165 Hom.: 2283

Bravo AF: 0.125

TwinsUK AF: 0.172 AC: 639

ALSPAC AF: 0.179 AC: 691

ESP6500AA AF: 0.0461 AC: 203

ESP6500EA AF: 0.167 AC: 1438

ExAC AF: 0.146 AC: 17709

Asia WGS AF: 0.103 AC: 360 AN: 3478

EpiCase AF: 0.177

EpiControl AF: 0.186

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 18, 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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 19, 2019

This variant is associated with the following publications: (PMID: 30389748) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	18
Dann	Uncertain	0.98
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.66	T;T
MetaRNN	Benign	0.0015	T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.35	T
Vest4		0.14
ClinPred		0.059	T
GERP RS		3.0
Varity_R		0.71
gMVP		0.38

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: rs61742072; hg19: chr17-76433899; COSMIC: COSV67750624;