rs140275399

Variant names:

• chr3-52353165-G-A
• rs140275399
• NM_015512.5:c.3090G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-52353165-G-A
• chr3-52353165-G-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_015512.5(DNAH1):​c.3090G>A​(p.Ala1030Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00607 in 1,614,012 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1030A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0043 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0063 (72 hom.)
• Consequence: DNAH1 NM_015512.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.00900
• 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: 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 3-52353165-G-A is Benign according to our data. Variant chr3-52353165-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 478437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.009 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00435 (662/152344) while in subpopulation SAS AF = 0.0232 (112/4830). AF 95% confidence interval is 0.0197. There are 5 homozygotes in GnomAd4. There are 337 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH1	NM_015512.5	c.3090G>A	p.Ala1030Ala	synonymous_variant	Exon 19 of 78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2	c.3090G>A	p.Ala1030Ala	synonymous_variant	Exon 20 of 80		XP_016861618.1
DNAH1	XM_017006130.2	c.3090G>A	p.Ala1030Ala	synonymous_variant	Exon 20 of 79		XP_016861619.1
DNAH1	XM_017006131.2	c.3090G>A	p.Ala1030Ala	synonymous_variant	Exon 20 of 79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7	c.3090G>A	p.Ala1030Ala	synonymous_variant	Exon 19 of 78	1	NM_015512.5	ENSP00000401514.2
DNAH1	ENST00000486752.5	n.3351G>A		non_coding_transcript_exon_variant	Exon 19 of 77	2
DNAH1	ENST00000497875.1	n.3255G>A		non_coding_transcript_exon_variant	Exon 20 of 21	2

Frequencies

GnomAD3 genomes AF: 0.00436 AC: 663 AN: 152226 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00191

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.0123

Gnomad SAS AF: 0.0234

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00476

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00648 AC: 1615 AN: 249082 AF XY: 0.00750

Gnomad AFR exome AF: 0.00174

Gnomad AMR exome AF: 0.00325

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.0124

Gnomad FIN exome AF: 0.00158

Gnomad NFE exome AF: 0.00422

Gnomad OTH exome AF: 0.00298

GnomAD4 exome AF: 0.00626 AC: 9143 AN: 1461668 Hom.: 72 Cov.: 31 AF XY: 0.00677 AC XY: 4923 AN XY: 727118

African (AFR) AF: 0.00176 AC: 59 AN: 33480

American (AMR) AF: 0.00300 AC: 134 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00168 AC: 44 AN: 26136

East Asian (EAS) AF: 0.0175 AC: 694 AN: 39700

South Asian (SAS) AF: 0.0233 AC: 2007 AN: 86256

European-Finnish (FIN) AF: 0.00152 AC: 81 AN: 53368

Middle Eastern (MID) AF: 0.00537 AC: 31 AN: 5768

European-Non Finnish (NFE) AF: 0.00512 AC: 5695 AN: 1111864

Other (OTH) AF: 0.00659 AC: 398 AN: 60374

GnomAD4 genome AF: 0.00435 AC: 662 AN: 152344 Hom.: 5 Cov.: 33 AF XY: 0.00452 AC XY: 337 AN XY: 74510

African (AFR) AF: 0.00190 AC: 79 AN: 41574

American (AMR) AF: 0.00340 AC: 52 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.0123 AC: 64 AN: 5184

South Asian (SAS) AF: 0.0232 AC: 112 AN: 4830

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00475 AC: 323 AN: 68032

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00382 Hom.: 2

Bravo AF: 0.00374

Asia WGS AF: 0.0110 AC: 39 AN: 3478

EpiCase AF: 0.00403

EpiControl AF: 0.00510

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Nov 28, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 09, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Jan 28, 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
BayesDel_noAF	Benign	-0.41
CADD	Benign	14
DANN	Benign	0.65
PhyloP100		0.0090
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs140275399; hg19: chr3-52387181; COSMIC: COSV101325241;