rs115647631

Positions:

• chr3-52393475-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_015512.5(DNAH1):​c.10616A>G​(p.Lys3539Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000157 in 1,614,038 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00092 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000077 (1 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.57

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011842728).
• BP6: Variant 3-52393475-A-G is Benign according to our data. Variant chr3-52393475-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 544674.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH1	NM_015512.5	c.10616A>G	p.Lys3539Arg	missense_variant	66/78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2	c.10685A>G	p.Lys3562Arg	missense_variant	68/80		XP_016861618.1
DNAH1	XM_017006130.2	c.10616A>G	p.Lys3539Arg	missense_variant	67/79		XP_016861619.1
DNAH1	XM_017006131.2	c.10559A>G	p.Lys3520Arg	missense_variant	67/79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7	c.10616A>G	p.Lys3539Arg	missense_variant	66/78	1	NM_015512.5	ENSP00000401514.2
DNAH1	ENST00000486752.5	n.11073A>G		non_coding_transcript_exon_variant	65/77	2
DNAH1	ENST00000488988.5	n.2402A>G		non_coding_transcript_exon_variant	13/25	2
DNAH1	ENST00000490713.5	n.1316A>G		non_coding_transcript_exon_variant	9/20	5		ENSP00000419071.1

Frequencies

GnomAD3 genomes AF: 0.000920 AC: 140 AN: 152242 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00287

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000185 AC: 46 AN: 249164 Hom.: 0 AF XY: 0.000163 AC XY: 22 AN XY: 135202

Gnomad AFR exome AF: 0.00239

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.0000773 AC: 113 AN: 1461678 Hom.: 1 Cov.: 32 AF XY: 0.0000660 AC XY: 48 AN XY: 727124

Gnomad4 AFR exome AF: 0.00221

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.000919 AC: 140 AN: 152360 Hom.: 1 Cov.: 32 AF XY: 0.000846 AC XY: 63 AN XY: 74506

Gnomad4 AFR AF: 0.00286

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000197 Hom.: 0

Bravo AF: 0.00114

ESP6500AA AF: 0.00266 AC: 11

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000231 AC: 28

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 08, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	19
DANN	Benign	0.97
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.062
Sift	Benign	0.46	T
Sift4G	Benign	0.51	T
Vest4		0.23
MVP		0.42
MPC		0.10
ClinPred		0.020	T
GERP RS		3.3
gMVP		0.35

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: rs115647631; hg19: chr3-52427491;