rs690844

Positions:

• chr17-78501838-C-A
• chr17-78501838-C-G

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.5226G>T​(p.Met1742Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.649 in 1,613,752 control chromosomes in the GnomAD database, including 343,917 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (34233 hom., cov: 33)
  • Exomes 𝑓: 0.65 (309684 hom.)
• Consequence: DNAH17 NM_173628.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.43

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-AS1 (HGNC:48594): (DNAH17 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.7439837E-7).
• BP6: Variant 17-78501838-C-A is Benign according to our data. Variant chr17-78501838-C-A is described in ClinVar as [Benign]. Clinvar id is 402686.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.927 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH17	NM_173628.4	c.5226G>T	p.Met1742Ile	missense_variant	34/81	ENST00000389840.7	NP_775899.3
DNAH17-AS1	NR_102401.1	n.3945C>A		non_coding_transcript_exon_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH17	ENST00000389840.7	c.5226G>T	p.Met1742Ile	missense_variant	34/81	5	NM_173628.4	ENSP00000374490	P1
DNAH17-AS1	ENST00000598378.2	n.3379C>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.667 AC: 101338 AN: 152022 Hom.: 34195 Cov.: 33

Gnomad AFR AF: 0.687

Gnomad AMI AF: 0.621

Gnomad AMR AF: 0.733

Gnomad ASJ AF: 0.652

Gnomad EAS AF: 0.949

Gnomad SAS AF: 0.710

Gnomad FIN AF: 0.671

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.615

Gnomad OTH AF: 0.670

GnomAD3 exomes AF: 0.691 AC: 172182 AN: 249262 Hom.: 60965 AF XY: 0.683 AC XY: 92342 AN XY: 135174

Gnomad AFR exome AF: 0.687

Gnomad AMR exome AF: 0.813

Gnomad ASJ exome AF: 0.652

Gnomad EAS exome AF: 0.952

Gnomad SAS exome AF: 0.702

Gnomad FIN exome AF: 0.677

Gnomad NFE exome AF: 0.617

Gnomad OTH exome AF: 0.659

GnomAD4 exome AF: 0.647 AC: 945213 AN: 1461612 Hom.: 309684 Cov.: 65 AF XY: 0.647 AC XY: 470506 AN XY: 727082

Gnomad4 AFR exome AF: 0.693

Gnomad4 AMR exome AF: 0.805

Gnomad4 ASJ exome AF: 0.653

Gnomad4 EAS exome AF: 0.966

Gnomad4 SAS exome AF: 0.700

Gnomad4 FIN exome AF: 0.675

Gnomad4 NFE exome AF: 0.621

Gnomad4 OTH exome AF: 0.659

GnomAD4 genome AF: 0.667 AC: 101428 AN: 152140 Hom.: 34233 Cov.: 33 AF XY: 0.671 AC XY: 49927 AN XY: 74378

Gnomad4 AFR AF: 0.687

Gnomad4 AMR AF: 0.733

Gnomad4 ASJ AF: 0.652

Gnomad4 EAS AF: 0.949

Gnomad4 SAS AF: 0.710

Gnomad4 FIN AF: 0.671

Gnomad4 NFE AF: 0.615

Gnomad4 OTH AF: 0.673

Alfa AF: 0.636 Hom.: 65763

Bravo AF: 0.675

TwinsUK AF: 0.642 AC: 2379

ALSPAC AF: 0.619 AC: 2385

ESP6500AA AF: 0.695 AC: 3042

ESP6500EA AF: 0.616 AC: 5283

ExAC AF: 0.682 AC: 82618

Asia WGS AF: 0.800 AC: 2781 AN: 3478

EpiCase AF: 0.613

EpiControl AF: 0.609

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 17, 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	0.13
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.0020
DANN	Benign	0.86
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.49	T;T
MetaRNN	Benign	5.7e-7	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.99	P;P
PrimateAI	Uncertain	0.52	T
REVEL	Benign	0.0060
Vest4		0.037
ClinPred		0.000081	T
GERP RS		-2.5
Varity_R		0.12
gMVP		0.10

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: rs690844; hg19: chr17-76497920; COSMIC: COSV67754477; COSMIC: COSV67754477;