rs61734631

Variant names:

• chr3-52383924-A-G
• rs61734631
• NM_015512.5:c.8215A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015512.5(DNAH1):​c.8215A>G​(p.Ile2739Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00157 in 1,613,528 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (12 hom., cov: 33)
  • Exomes 𝑓: 0.00093 (20 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.40

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009954423).
• BP6: Variant 3-52383924-A-G is Benign according to our data. Variant chr3-52383924-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 478498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00773 (1177/152302) while in subpopulation AFR AF= 0.0261 (1083/41558). AF 95% confidence interval is 0.0248. There are 12 homozygotes in gnomad4. There are 555 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH1	NM_015512.5	c.8215A>G	p.Ile2739Val	missense_variant	Exon 52 of 78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2	c.8284A>G	p.Ile2762Val	missense_variant	Exon 54 of 80		XP_016861618.1
DNAH1	XM_017006130.2	c.8215A>G	p.Ile2739Val	missense_variant	Exon 53 of 79		XP_016861619.1
DNAH1	XM_017006131.2	c.8284A>G	p.Ile2762Val	missense_variant	Exon 54 of 79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7	c.8215A>G	p.Ile2739Val	missense_variant	Exon 52 of 78	1	NM_015512.5	ENSP00000401514.2
DNAH1	ENST00000486752.5	n.8476A>G		non_coding_transcript_exon_variant	Exon 52 of 77	2

Frequencies

GnomAD3 genomes AF: 0.00773 AC: 1176 AN: 152184 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.0261

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00191 AC: 474 AN: 248230 Hom.: 5 AF XY: 0.00148 AC XY: 200 AN XY: 134746

Gnomad AFR exome AF: 0.0240

Gnomad AMR exome AF: 0.00175

Gnomad ASJ exome AF: 0.000599

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000985

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000267

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000929 AC: 1357 AN: 1461226 Hom.: 20 Cov.: 31 AF XY: 0.000861 AC XY: 626 AN XY: 726848

Gnomad4 AFR exome AF: 0.0254

Gnomad4 AMR exome AF: 0.00188

Gnomad4 ASJ exome AF: 0.000728

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000219

Gnomad4 OTH exome AF: 0.00191

GnomAD4 genome AF: 0.00773 AC: 1177 AN: 152302 Hom.: 12 Cov.: 33 AF XY: 0.00745 AC XY: 555 AN XY: 74464

Gnomad4 AFR AF: 0.0261

Gnomad4 AMR AF: 0.00418

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00170 Hom.: 7

Bravo AF: 0.00899

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0238 AC: 93

ESP6500EA AF: 0.000603 AC: 5

ExAC AF: 0.00219 AC: 265

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.000297

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 05, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spermatogenic failure 18;C4539798:Ciliary dyskinesia, primary, 37 Benign:1

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.50	T
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.15
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.62
MVP		0.64
MPC		0.51
ClinPred		0.033	T
GERP RS		4.2
gMVP		0.38

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

Publications

LitVar

Other links and lift over

dbSNP: rs61734631; hg19: chr3-52417940;