rs35982798

Positions:

• chr3-52349324-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_015512.5(DNAH1):​c.2430C>T​(p.Thr810Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0423 in 1,613,948 control chromosomes in the GnomAD database, including 1,663 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (134 hom., cov: 33)
  • Exomes 𝑓: 0.043 (1529 hom.)
• Consequence: DNAH1 NM_015512.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -5.32

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 3-52349324-C-T is Benign according to our data. Variant chr3-52349324-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 478430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.32 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0345 (5256/152268) while in subpopulation NFE AF= 0.0465 (3161/68010). AF 95% confidence interval is 0.0451. There are 134 homozygotes in gnomad4. There are 2417 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 134 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH1	NM_015512.5	c.2430C>T	p.Thr810Thr	synonymous_variant	14/78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2	c.2430C>T	p.Thr810Thr	synonymous_variant	15/80		XP_016861618.1
DNAH1	XM_017006130.2	c.2430C>T	p.Thr810Thr	synonymous_variant	15/79		XP_016861619.1
DNAH1	XM_017006131.2	c.2430C>T	p.Thr810Thr	synonymous_variant	15/79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7	c.2430C>T	p.Thr810Thr	synonymous_variant	14/78	1	NM_015512.5	ENSP00000401514.2
DNAH1	ENST00000486752.5	n.2691C>T		non_coding_transcript_exon_variant	14/77	2
DNAH1	ENST00000497875.1	n.2595C>T		non_coding_transcript_exon_variant	15/21	2

Frequencies

GnomAD3 genomes AF: 0.0345 AC: 5255 AN: 152150 Hom.: 133 Cov.: 33

Gnomad AFR AF: 0.0137

Gnomad AMI AF: 0.0866

Gnomad AMR AF: 0.0461

Gnomad ASJ AF: 0.0288

Gnomad EAS AF: 0.0218

Gnomad SAS AF: 0.0222

Gnomad FIN AF: 0.0305

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0465

Gnomad OTH AF: 0.0416

GnomAD3 exomes AF: 0.0354 AC: 8821 AN: 249214 Hom.: 189 AF XY: 0.0357 AC XY: 4822 AN XY: 135204

Gnomad AFR exome AF: 0.0141

Gnomad AMR exome AF: 0.0339

Gnomad ASJ exome AF: 0.0276

Gnomad EAS exome AF: 0.0180

Gnomad SAS exome AF: 0.0197

Gnomad FIN exome AF: 0.0326

Gnomad NFE exome AF: 0.0465

Gnomad OTH exome AF: 0.0453

GnomAD4 exome AF: 0.0431 AC: 63040 AN: 1461680 Hom.: 1529 Cov.: 34 AF XY: 0.0428 AC XY: 31101 AN XY: 727128

Gnomad4 AFR exome AF: 0.0143

Gnomad4 AMR exome AF: 0.0363

Gnomad4 ASJ exome AF: 0.0283

Gnomad4 EAS exome AF: 0.0167

Gnomad4 SAS exome AF: 0.0201

Gnomad4 FIN exome AF: 0.0335

Gnomad4 NFE exome AF: 0.0478

Gnomad4 OTH exome AF: 0.0445

GnomAD4 genome AF: 0.0345 AC: 5256 AN: 152268 Hom.: 134 Cov.: 33 AF XY: 0.0325 AC XY: 2417 AN XY: 74458

Gnomad4 AFR AF: 0.0136

Gnomad4 AMR AF: 0.0460

Gnomad4 ASJ AF: 0.0288

Gnomad4 EAS AF: 0.0214

Gnomad4 SAS AF: 0.0220

Gnomad4 FIN AF: 0.0305

Gnomad4 NFE AF: 0.0465

Gnomad4 OTH AF: 0.0435

Alfa AF: 0.0412 Hom.: 76

Bravo AF: 0.0355

Asia WGS AF: 0.0360 AC: 124 AN: 3478

EpiCase AF: 0.0479

EpiControl AF: 0.0519

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.052
DANN	Benign	0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs35982798; hg19: chr3-52383340;