17-78529677-G-C

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.3302C>G(p.Ala1101Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 1,613,568 control chromosomes in the GnomAD database, including 27,216 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1858 hom., cov: 31)
  • Exomes 𝑓: 0.18 (25358 hom.)
• Consequence: DNAH17 NM_173628.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.526

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=0.004291922).
• BP6: Variant 17-78529677-G-C is Benign according to our data. Variant chr17-78529677-G-C is described in ClinVar as [Benign]. Clinvar id is 402695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH17	NM_173628.4	c.3302C>G	p.Ala1101Gly	missense_variant	22/81	ENST00000389840.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH17	ENST00000389840.7	c.3302C>G	p.Ala1101Gly	missense_variant	22/81	5	NM_173628.4	P1

Frequencies

GnomAD3 genomes AF: 0.138 AC: 21040 AN: 152000 Hom.: 1857 Cov.: 31

Gnomad AFR AF: 0.0421

Gnomad AMI AF: 0.282

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.114

Gnomad SAS AF: 0.210

Gnomad FIN AF: 0.0988

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.187

Gnomad OTH AF: 0.157

GnomAD3 exomes AF: 0.168 AC: 41880 AN: 249026 Hom.: 3993 AF XY: 0.171 AC XY: 23101 AN XY: 135102

Gnomad AFR exome AF: 0.0343

Gnomad AMR exome AF: 0.221

Gnomad ASJ exome AF: 0.128

Gnomad EAS exome AF: 0.109

Gnomad SAS exome AF: 0.220

Gnomad FIN exome AF: 0.103

Gnomad NFE exome AF: 0.182

Gnomad OTH exome AF: 0.153

GnomAD4 exome AF: 0.182 AC: 265621 AN: 1461450 Hom.: 25358 Cov.: 44 AF XY: 0.182 AC XY: 132509 AN XY: 727014

Gnomad4 AFR exome AF: 0.0336

Gnomad4 AMR exome AF: 0.214

Gnomad4 ASJ exome AF: 0.129

Gnomad4 EAS exome AF: 0.106

Gnomad4 SAS exome AF: 0.223

Gnomad4 FIN exome AF: 0.107

Gnomad4 NFE exome AF: 0.190

Gnomad4 OTH exome AF: 0.170

GnomAD4 genome AF: 0.138 AC: 21049 AN: 152118 Hom.: 1858 Cov.: 31 AF XY: 0.137 AC XY: 10215 AN XY: 74360

Gnomad4 AFR AF: 0.0420

Gnomad4 AMR AF: 0.189

Gnomad4 ASJ AF: 0.125

Gnomad4 EAS AF: 0.115

Gnomad4 SAS AF: 0.209

Gnomad4 FIN AF: 0.0988

Gnomad4 NFE AF: 0.187

Gnomad4 OTH AF: 0.157

Alfa AF: 0.166 Hom.: 1830

Bravo AF: 0.141

TwinsUK AF: 0.198 AC: 736

ALSPAC AF: 0.208 AC: 803

ESP6500AA AF: 0.0421 AC: 164

ESP6500EA AF: 0.191 AC: 1576

ExAC AF: 0.165 AC: 19998

Asia WGS AF: 0.154 AC: 532 AN: 3478

EpiCase AF: 0.189

EpiControl AF: 0.188

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

Oct 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	5.5
Dann	Benign	0.80
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.83	T;T
MetaRNN	Benign	0.0043	T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.23	T
Vest4		0.044
ClinPred		0.00018	T
GERP RS		1.4
Varity_R		0.032
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61741523; hg19: chr17-76525759; COSMIC: COSV67751204; COSMIC: COSV67751204;