17-78437816-T-C

Variant names:

• chr17-78437816-T-C
• rs12941494
• NM_173628.4:c.11858A>G

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.11858A>G​(p.His3953Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.991 in 1,612,240 control chromosomes in the GnomAD database, including 792,214 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 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. H3953Y) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.95 (69689 hom., cov: 33)
  • Exomes 𝑓: 0.99 (722525 hom.)
• Consequence: DNAH17 NM_173628.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.135
• Publications: 21 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=6.583821E-7).
• BP6: Variant 17-78437816-T-C is Benign according to our data. Variant chr17-78437816-T-C is described in ClinVar as Benign. ClinVar VariationId is 402674.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 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.11858A>G	p.His3953Arg	missense	Exon 74 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.11858A>G	p.His3953Arg	missense	Exon 74 of 81	ENSP00000374490.6
	DNAH17	ENST00000586052.5	TSL:5	n.4994A>G		non_coding_transcript_exon	Exon 28 of 35
	DNAH17	ENST00000590227.5	TSL:2	n.1532A>G		non_coding_transcript_exon	Exon 6 of 13

Frequencies

GnomAD3 genomes AF: 0.954 AC: 145230 AN: 152158 Hom.: 69664 Cov.: 33

Gnomad AFR AF: 0.847

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.977

Gnomad ASJ AF: 0.970

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.984

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.956

GnomAD2 exomes AF: 0.987 AC: 245818 AN: 249138 AF XY: 0.990

Gnomad AFR exome AF: 0.842

Gnomad AMR exome AF: 0.989

Gnomad ASJ exome AF: 0.976

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.999

Gnomad OTH exome AF: 0.990

GnomAD4 exome AF: 0.995 AC: 1452017 AN: 1459964 Hom.: 722525 Cov.: 56 AF XY: 0.995 AC XY: 722794 AN XY: 726246

African (AFR) AF: 0.839 AC: 28091 AN: 33470

American (AMR) AF: 0.988 AC: 44180 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.974 AC: 25444 AN: 26116

East Asian (EAS) AF: 1.00 AC: 39682 AN: 39684

South Asian (SAS) AF: 1.00 AC: 86169 AN: 86208

European-Finnish (FIN) AF: 1.00 AC: 52080 AN: 52082

Middle Eastern (MID) AF: 0.993 AC: 5717 AN: 5760

European-Non Finnish (NFE) AF: 1.00 AC: 1111146 AN: 1111622

Other (OTH) AF: 0.986 AC: 59508 AN: 60326

GnomAD4 genome AF: 0.954 AC: 145307 AN: 152276 Hom.: 69689 Cov.: 33 AF XY: 0.956 AC XY: 71138 AN XY: 74442

African (AFR) AF: 0.847 AC: 35169 AN: 41528

American (AMR) AF: 0.977 AC: 14945 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.970 AC: 3367 AN: 3470

East Asian (EAS) AF: 0.999 AC: 5183 AN: 5186

South Asian (SAS) AF: 0.999 AC: 4820 AN: 4824

European-Finnish (FIN) AF: 1.00 AC: 10625 AN: 10626

Middle Eastern (MID) AF: 0.986 AC: 290 AN: 294

European-Non Finnish (NFE) AF: 0.999 AC: 67978 AN: 68028

Other (OTH) AF: 0.955 AC: 2018 AN: 2114

Alfa AF: 0.977 Hom.: 137541

Bravo AF: 0.947

TwinsUK AF: 0.999 AC: 3704

ALSPAC AF: 1.00 AC: 3853

ESP6500AA AF: 0.848 AC: 3733

ESP6500EA AF: 0.998 AC: 8580

ExAC AF: 0.985 AC: 119093

Asia WGS AF: 0.980 AC: 3407 AN: 3478

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	0.056
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.86
DANN	Benign	0.28
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.060	T
MetaRNN	Benign	6.6e-7	T
MetaSVM	Benign	-0.93	T
PhyloP100		-0.14
PrimateAI	Benign	0.34	T
PROVEAN	Pathogenic	-7.1	D
REVEL	Benign	0.12
Sift	Uncertain	0.0010	D
Vest4		0.027
ClinPred		0.041	T
GERP RS		4.1
Varity_R		0.44
gMVP		0.34
Mutation Taster		=99/1	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: rs12941494; hg19: chr17-76433898; COSMIC: COSV101102701;