NM_173628.4:c.3659G>A

Variant names:

• chr17-78526703-C-T
• rs61744544
• NM_173628.4:c.3659G>A

Variant summary

Our verdict is Benign. The variant received -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. 15/20 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 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
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• spermatogenic failure 39

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• non-syndromic male infertility due to sperm motility disorder

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173628.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH17	NM_173628.4	MANE Select	c.3659G>A	p.Arg1220His	missense	Exon 24 of 81	NP_775899.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH17	ENST00000389840.7	TSL:5 MANE Select	c.3659G>A	p.Arg1220His	missense	Exon 24 of 81	ENSP00000374490.6

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

GnomAD2 exomes AF: 0.153 AC: 37748 AN: 247438 AF XY: 0.154

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 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

African (AFR) AF: 0.0291 AC: 973 AN: 33410

American (AMR) AF: 0.170 AC: 7551 AN: 44374

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 6091 AN: 25984

East Asian (EAS) AF: 0.0645 AC: 2554 AN: 39586

South Asian (SAS) AF: 0.0938 AC: 8066 AN: 85970

European-Finnish (FIN) AF: 0.163 AC: 8715 AN: 53360

Middle Eastern (MID) AF: 0.206 AC: 1175 AN: 5714

European-Non Finnish (NFE) AF: 0.171 AC: 189602 AN: 1108908

Other (OTH) AF: 0.156 AC: 9386 AN: 60130

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

African (AFR) AF: 0.0345 AC: 1435 AN: 41540

American (AMR) AF: 0.166 AC: 2543 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.228 AC: 791 AN: 3470

East Asian (EAS) AF: 0.0708 AC: 366 AN: 5172

South Asian (SAS) AF: 0.0871 AC: 420 AN: 4824

European-Finnish (FIN) AF: 0.162 AC: 1720 AN: 10596

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.181 AC: 12320 AN: 67988

Other (OTH) AF: 0.157 AC: 332 AN: 2112

Alfa AF: 0.166 Hom.: 4414

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	DNAH17-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.6	L
PhyloP100		-2.1
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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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