chr17-78437817-G-A

Variant names:

• chr17-78437817-G-A
• rs61742072
• NM_173628.4:c.11857C>T

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.11857C>T​(p.His3953Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 1,611,708 control chromosomes in the GnomAD database, including 22,566 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H3953R) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.13 (1506 hom., cov: 29)
  • Exomes 𝑓: 0.17 (21060 hom.)
• Consequence: DNAH17 NM_173628.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.63
• Publications: 15 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=0.0015000999).
• BP6: Variant 17-78437817-G-A is Benign according to our data. Variant chr17-78437817-G-A is described in ClinVar as Benign. ClinVar VariationId is 402675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.173 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH17	NM_173628.4	MANE Select	c.11857C>T	p.His3953Tyr	missense	Exon 74 of 81	NP_775899.3	Q9UFH2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH17	ENST00000389840.7	TSL:5 MANE Select	c.11857C>T	p.His3953Tyr	missense	Exon 74 of 81	ENSP00000374490.6	Q9UFH2-1
	DNAH17	ENST00000586052.5	TSL:5	n.4993C>T		non_coding_transcript_exon	Exon 28 of 35
	DNAH17	ENST00000590227.5	TSL:2	n.1531C>T		non_coding_transcript_exon	Exon 6 of 13

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19476 AN: 152112 Hom.: 1505 Cov.: 29

Gnomad AFR AF: 0.0523

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.199

Gnomad EAS AF: 0.0943

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.147

GnomAD2 exomes AF: 0.142 AC: 35251 AN: 248778 AF XY: 0.149

Gnomad AFR exome AF: 0.0427

Gnomad AMR exome AF: 0.0837

Gnomad ASJ exome AF: 0.197

Gnomad EAS exome AF: 0.0925

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.178

Gnomad OTH exome AF: 0.165

GnomAD4 exome AF: 0.165 AC: 240842 AN: 1459478 Hom.: 21060 Cov.: 35 AF XY: 0.165 AC XY: 119862 AN XY: 725962

African (AFR) AF: 0.0447 AC: 1495 AN: 33466

American (AMR) AF: 0.0860 AC: 3842 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.203 AC: 5287 AN: 26098

East Asian (EAS) AF: 0.0773 AC: 3065 AN: 39660

South Asian (SAS) AF: 0.154 AC: 13265 AN: 86166

European-Finnish (FIN) AF: 0.114 AC: 5929 AN: 52052

Middle Eastern (MID) AF: 0.200 AC: 1151 AN: 5760

European-Non Finnish (NFE) AF: 0.178 AC: 197380 AN: 1111282

Other (OTH) AF: 0.156 AC: 9428 AN: 60316

GnomAD4 genome AF: 0.128 AC: 19476 AN: 152230 Hom.: 1506 Cov.: 29 AF XY: 0.125 AC XY: 9282 AN XY: 74448

African (AFR) AF: 0.0524 AC: 2176 AN: 41542

American (AMR) AF: 0.115 AC: 1756 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 690 AN: 3468

East Asian (EAS) AF: 0.0939 AC: 487 AN: 5186

South Asian (SAS) AF: 0.150 AC: 724 AN: 4822

European-Finnish (FIN) AF: 0.112 AC: 1194 AN: 10614

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.175 AC: 11925 AN: 67980

Other (OTH) AF: 0.146 AC: 308 AN: 2116

Alfa AF: 0.155 Hom.: 3361

Bravo AF: 0.125

TwinsUK AF: 0.172 AC: 639

ALSPAC AF: 0.179 AC: 691

ESP6500AA AF: 0.0461 AC: 203

ESP6500EA AF: 0.167 AC: 1438

ExAC AF: 0.146 AC: 17709

Asia WGS AF: 0.103 AC: 360 AN: 3478

EpiCase AF: 0.177

EpiControl AF: 0.186

ClinVar

ClinVar submissions

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	0.078
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.97	T
PhyloP100		2.6
PrimateAI	Benign	0.35	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Benign	0.084
Sift	Pathogenic	0.0	D
Vest4		0.14
ClinPred		0.059	T
GERP RS		3.0
Varity_R		0.71
gMVP		0.38
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: rs61742072; hg19: chr17-76433899; COSMIC: COSV67750624;