chr17-78526703-C-T

Position:

• chr17-78526703-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.3659G>A​(p.Arg1220His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,609,628 control chromosomes in the GnomAD database, including 21,556 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R1220R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.13 (1728 hom., cov: 33)
  • Exomes 𝑓: 0.16 (19828 hom.)
• Consequence: DNAH17 NM_173628.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.12

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=0.0034236312).
• BP6: Variant 17-78526703-C-T is Benign according to our data. Variant chr17-78526703-C-T is described in ClinVar as [Benign]. Clinvar id is 402693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.179 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH17	NM_173628.4	c.3659G>A	p.Arg1220His	missense_variant	24/81	ENST00000389840.7	NP_775899.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH17	ENST00000389840.7	c.3659G>A	p.Arg1220His	missense_variant	24/81	5	NM_173628.4	ENSP00000374490	P1

Frequencies

GnomAD3 genomes AF: 0.132 AC: 20119 AN: 152074 Hom.: 1728 Cov.: 33

Gnomad AFR AF: 0.0345

Gnomad AMI AF: 0.144

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.228

Gnomad EAS AF: 0.0708

Gnomad SAS AF: 0.0878

Gnomad FIN AF: 0.162

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.181

Gnomad OTH AF: 0.159

GnomAD3 exomes AF: 0.153 AC: 37748 AN: 247438 Hom.: 3238 AF XY: 0.154 AC XY: 20653 AN XY: 134242

Gnomad AFR exome AF: 0.0297

Gnomad AMR exome AF: 0.166

Gnomad ASJ exome AF: 0.236

Gnomad EAS exome AF: 0.0731

Gnomad SAS exome AF: 0.0909

Gnomad FIN exome AF: 0.162

Gnomad NFE exome AF: 0.184

Gnomad OTH exome AF: 0.185

GnomAD4 exome AF: 0.161 AC: 234113 AN: 1457436 Hom.: 19828 Cov.: 32 AF XY: 0.160 AC XY: 115922 AN XY: 724380

Gnomad4 AFR exome AF: 0.0291

Gnomad4 AMR exome AF: 0.170

Gnomad4 ASJ exome AF: 0.234

Gnomad4 EAS exome AF: 0.0645

Gnomad4 SAS exome AF: 0.0938

Gnomad4 FIN exome AF: 0.163

Gnomad4 NFE exome AF: 0.171

Gnomad4 OTH exome AF: 0.156

GnomAD4 genome AF: 0.132 AC: 20124 AN: 152192 Hom.: 1728 Cov.: 33 AF XY: 0.130 AC XY: 9696 AN XY: 74404

Gnomad4 AFR AF: 0.0345

Gnomad4 AMR AF: 0.166

Gnomad4 ASJ AF: 0.228

Gnomad4 EAS AF: 0.0708

Gnomad4 SAS AF: 0.0871

Gnomad4 FIN AF: 0.162

Gnomad4 NFE AF: 0.181

Gnomad4 OTH AF: 0.157

Alfa AF: 0.173 Hom.: 3687

Bravo AF: 0.129

TwinsUK AF: 0.168 AC: 622

ALSPAC AF: 0.162 AC: 626

ESP6500AA AF: 0.0308 AC: 121

ESP6500EA AF: 0.176 AC: 1456

ExAC AF: 0.151 AC: 18206

Asia WGS AF: 0.0610 AC: 212 AN: 3478

EpiCase AF: 0.194

EpiControl AF: 0.186

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	0.068
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.34
DANN	Benign	0.93
DEOGEN2	Benign	0.048	.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.66	T;T
MetaRNN	Benign	0.0034	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.6	.;L
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-2.3	.;N
REVEL	Benign	0.0090
Sift	Benign	0.063	.;T
Vest4		0.077
ClinPred		0.0073	T
GERP RS		-7.9
Varity_R		0.030
gMVP		0.18

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: rs61744544; hg19: chr17-76522785; COSMIC: COSV67751247; COSMIC: COSV67751247;