NM_015512.5:c.6191A>G

Variant names:

• chr3-52370162-A-G
• rs145673040
• NM_015512.5:c.6191A>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.6191A>G​(p.Asn2064Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,613,844 control chromosomes in the GnomAD database, including 172 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0094 (14 hom., cov: 33)
  • Exomes 𝑓: 0.011 (158 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 8.06
• Publications: 3 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: ClinGen, Labcorp Genetics (formerly Invitae)
• ciliary dyskinesia, primary, 37

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen
• 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=0.003696978).
• BP6: Variant 3-52370162-A-G is Benign according to our data. Variant chr3-52370162-A-G is described in ClinVar as Benign. ClinVar VariationId is 478474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00941 (1432/152190) while in subpopulation NFE AF = 0.00969 (659/67988). AF 95% confidence interval is 0.00908. There are 14 homozygotes in GnomAd4. There are 826 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH1	NM_015512.5	MANE Select	c.6191A>G	p.Asn2064Ser	missense	Exon 39 of 78	NP_056327.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH1	ENST00000420323.7	TSL:1 MANE Select	c.6191A>G	p.Asn2064Ser	missense	Exon 39 of 78	ENSP00000401514.2
	DNAH1	ENST00000486752.5	TSL:2	n.6452A>G		non_coding_transcript_exon	Exon 39 of 77

Frequencies

GnomAD3 genomes AF: 0.00941 AC: 1431 AN: 152072 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.00179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.00866

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.0536

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00969

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.0106 AC: 2640 AN: 249192 AF XY: 0.0110

Gnomad AFR exome AF: 0.00174

Gnomad AMR exome AF: 0.00287

Gnomad ASJ exome AF: 0.00626

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0507

Gnomad NFE exome AF: 0.00963

Gnomad OTH exome AF: 0.0122

GnomAD4 exome AF: 0.0107 AC: 15670 AN: 1461654 Hom.: 158 Cov.: 32 AF XY: 0.0106 AC XY: 7702 AN XY: 727108

African (AFR) AF: 0.00143 AC: 48 AN: 33480

American (AMR) AF: 0.00315 AC: 141 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00704 AC: 184 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00674 AC: 581 AN: 86256

European-Finnish (FIN) AF: 0.0479 AC: 2560 AN: 53392

Middle Eastern (MID) AF: 0.0118 AC: 68 AN: 5768

European-Non Finnish (NFE) AF: 0.0103 AC: 11421 AN: 1111842

Other (OTH) AF: 0.0110 AC: 667 AN: 60372

GnomAD4 genome AF: 0.00941 AC: 1432 AN: 152190 Hom.: 14 Cov.: 33 AF XY: 0.0111 AC XY: 826 AN XY: 74420

African (AFR) AF: 0.00178 AC: 74 AN: 41526

American (AMR) AF: 0.00392 AC: 60 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00866 AC: 30 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00539 AC: 26 AN: 4824

European-Finnish (FIN) AF: 0.0536 AC: 568 AN: 10602

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00969 AC: 659 AN: 67988

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00818 Hom.: 13

Bravo AF: 0.00618

TwinsUK AF: 0.0113 AC: 42

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.00231 AC: 10

ESP6500EA AF: 0.00914 AC: 78

ExAC AF: 0.0100 AC: 1214

Asia WGS AF: 0.00346 AC: 13 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNAH1: BP4, BS1, BS2

Oct 03, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	20
DANN	Uncertain	0.99
Eigen	Benign	-0.021
Eigen_PC	Benign	0.061
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-1.0	T
PhyloP100		8.1
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.12
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.047	D
Vest4		0.43
MPC		0.12
ClinPred		0.032	T
GERP RS		4.5
gMVP		0.20
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs145673040; hg19: chr3-52404178; COSMIC: COSV70235638; COSMIC: COSV70235638;