rs61734643

Variant names:

• chr3-52351976-A-G
• rs61734643
• NM_015512.5:c.2744A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015512.5(DNAH1):​c.2744A>G​(p.Asn915Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00556 in 1,602,576 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0058 (65 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.489
• Publications: 5 publications found

Genes affected

DNAH1 (HGNC:2940): (dynein axonemal heavy chain 1) This gene encodes an inner dynein arm heavy chain that provides structural support between the radial spokes and the outer doublet of the sperm tail. Naturally occurring mutations in this gene are associated with primary ciliary dyskinesia and multiple morphological anomalies of the flagella that result in asthenozoospermia and male infertility. Mice with a homozygous knockout of the orthologous gene are viable but have reduced sperm motility and are infertile. [provided by RefSeq, Feb 2017]

DNAH1 Gene-Disease associations (from GenCC):

• spermatogenic failure 18

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• ciliary dyskinesia, primary, 37

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• 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=0.007988453).
• BP6: Variant 3-52351976-A-G is Benign according to our data. Variant chr3-52351976-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 478434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00375 (571/152342) while in subpopulation SAS AF = 0.0232 (112/4828). AF 95% confidence interval is 0.0197. There are 4 homozygotes in GnomAd4. There are 290 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015512.5. 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
	DNAH1	NM_015512.5	MANE Select	c.2744A>G	p.Asn915Ser	missense	Exon 17 of 78	NP_056327.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH1	ENST00000420323.7	TSL:1 MANE Select	c.2744A>G	p.Asn915Ser	missense	Exon 17 of 78	ENSP00000401514.2	Q9P2D7-4
	DNAH1	ENST00000486752.5	TSL:2	n.3005A>G		non_coding_transcript_exon	Exon 17 of 77
	DNAH1	ENST00000497875.1	TSL:2	n.2909A>G		non_coding_transcript_exon	Exon 18 of 21

Frequencies

GnomAD3 genomes AF: 0.00376 AC: 572 AN: 152224 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000892

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00443

Gnomad SAS AF: 0.0234

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00475

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00555 AC: 1283 AN: 231132 AF XY: 0.00655

Gnomad AFR exome AF: 0.000888

Gnomad AMR exome AF: 0.00245

Gnomad ASJ exome AF: 0.00166

Gnomad EAS exome AF: 0.00349

Gnomad FIN exome AF: 0.00155

Gnomad NFE exome AF: 0.00403

Gnomad OTH exome AF: 0.00297

GnomAD4 exome AF: 0.00575 AC: 8342 AN: 1450234 Hom.: 65 Cov.: 31 AF XY: 0.00627 AC XY: 4513 AN XY: 720002

African (AFR) AF: 0.000663 AC: 22 AN: 33206

American (AMR) AF: 0.00227 AC: 98 AN: 43194

Ashkenazi Jewish (ASJ) AF: 0.00162 AC: 42 AN: 25858

East Asian (EAS) AF: 0.00372 AC: 146 AN: 39270

South Asian (SAS) AF: 0.0233 AC: 1946 AN: 83572

European-Finnish (FIN) AF: 0.00152 AC: 80 AN: 52676

Middle Eastern (MID) AF: 0.00532 AC: 30 AN: 5634

European-Non Finnish (NFE) AF: 0.00509 AC: 5639 AN: 1106836

Other (OTH) AF: 0.00565 AC: 339 AN: 59988

GnomAD4 genome AF: 0.00375 AC: 571 AN: 152342 Hom.: 4 Cov.: 32 AF XY: 0.00389 AC XY: 290 AN XY: 74490

African (AFR) AF: 0.000890 AC: 37 AN: 41582

American (AMR) AF: 0.00314 AC: 48 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00444 AC: 23 AN: 5182

South Asian (SAS) AF: 0.0232 AC: 112 AN: 4828

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00473 AC: 322 AN: 68034

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00400 Hom.: 10

Bravo AF: 0.00291

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000750 AC: 3

ESP6500EA AF: 0.00371 AC: 31

ExAC AF: 0.00564 AC: 681

Asia WGS AF: 0.00837 AC: 29 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Spermatogenic failure 18;C4539798:Ciliary dyskinesia, primary, 37 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	16
DANN	Benign	0.95
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-0.98	T
PhyloP100		0.49
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.082
Sift	Benign	0.49	T
Sift4G	Benign	0.42	T
Vest4		0.19
MVP		0.19
MPC		0.098
ClinPred		0.0058	T
GERP RS		4.4
gMVP		0.40
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs61734643; hg19: chr3-52385992; COSMIC: COSV107515688;