chr17-78484959-A-C

Position:

• chr17-78484959-A-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_173628.4(DNAH17):​c.7558T>G​(p.Phe2520Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00273 in 1,613,166 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0028 (6 hom.)
• Consequence: DNAH17 NM_173628.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 9.18

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02804926).
• BP6: Variant 17-78484959-A-C is Benign according to our data. Variant chr17-78484959-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2234915.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00227 (346/152286) while in subpopulation NFE AF= 0.00319 (217/68018). AF 95% confidence interval is 0.00284. There are 1 homozygotes in gnomad4. There are 192 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH17	NM_173628.4	c.7558T>G	p.Phe2520Val	missense_variant	48/81	ENST00000389840.7	NP_775899.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH17	ENST00000389840.7	c.7558T>G	p.Phe2520Val	missense_variant	48/81	5	NM_173628.4	ENSP00000374490.6

Frequencies

GnomAD3 genomes AF: 0.00227 AC: 346 AN: 152168 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00735

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00319

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00238 AC: 586 AN: 246670 Hom.: 4 AF XY: 0.00234 AC XY: 314 AN XY: 134128

Gnomad AFR exome AF: 0.000526

Gnomad AMR exome AF: 0.000904

Gnomad ASJ exome AF: 0.00110

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000264

Gnomad FIN exome AF: 0.00783

Gnomad NFE exome AF: 0.00314

Gnomad OTH exome AF: 0.00167

GnomAD4 exome AF: 0.00278 AC: 4062 AN: 1460880 Hom.: 6 Cov.: 32 AF XY: 0.00262 AC XY: 1902 AN XY: 726636

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000874

Gnomad4 ASJ exome AF: 0.000919

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.00737

Gnomad4 NFE exome AF: 0.00311

Gnomad4 OTH exome AF: 0.00202

GnomAD4 genome AF: 0.00227 AC: 346 AN: 152286 Hom.: 1 Cov.: 31 AF XY: 0.00258 AC XY: 192 AN XY: 74468

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00735

Gnomad4 NFE AF: 0.00319

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00244 Hom.: 0

Bravo AF: 0.00156

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000717 AC: 3

ESP6500EA AF: 0.00296 AC: 25

ExAC AF: 0.00242 AC: 293

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00256

EpiControl AF: 0.00190

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 04, 2022

The c.7558T>G (p.F2520V) alteration is located in exon 48 (coding exon 47) of the DNAH17 gene. This alteration results from a T to G substitution at nucleotide position 7558, causing the phenylalanine (F) at amino acid position 2520 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

DNAH17-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 19, 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

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2024

DNAH17: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.028	T;T
MetaSVM	Uncertain	0.30	D
PrimateAI	Uncertain	0.79	T
REVEL	Uncertain	0.64
Vest4		0.91
MVP		0.51
ClinPred		0.12	T
GERP RS		5.0
Varity_R		0.26
gMVP		0.77

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: rs200203879; hg19: chr17-76481041;