rs375828810

Positions:

• chr3-52364819-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_015512.5(DNAH1):​c.5332-14G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000751 in 1,610,956 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00078 (16 hom.)
• Consequence: DNAH1 NM_015512.5 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.00500

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 -16 ACMG points.

• BP6: Variant 3-52364819-G-A is Benign according to our data. Variant chr3-52364819-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 402606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000473 (72/152280) while in subpopulation SAS AF= 0.00871 (42/4822). AF 95% confidence interval is 0.00662. There are 0 homozygotes in gnomad4. There are 49 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH1	NM_015512.5	c.5332-14G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000420323.7
DNAH1	XM_017006129.2	c.5332-14G>A		splice_polypyrimidine_tract_variant, intron_variant
DNAH1	XM_017006130.2	c.5332-14G>A		splice_polypyrimidine_tract_variant, intron_variant
DNAH1	XM_017006131.2	c.5332-14G>A		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7	c.5332-14G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_015512.5	P1
DNAH1	ENST00000486752.5	n.5593-14G>A		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.000467 AC: 71 AN: 152162 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00850

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00149 AC: 370 AN: 247522 Hom.: 7 AF XY: 0.00204 AC XY: 274 AN XY: 134364

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000843

Gnomad ASJ exome AF: 0.000402

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00941

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000340

Gnomad OTH exome AF: 0.00200

GnomAD4 exome AF: 0.000780 AC: 1138 AN: 1458676 Hom.: 16 Cov.: 31 AF XY: 0.00109 AC XY: 787 AN XY: 725128

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000986

Gnomad4 ASJ exome AF: 0.000154

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00937

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000176

Gnomad4 OTH exome AF: 0.00110

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152280 Hom.: 0 Cov.: 33 AF XY: 0.000658 AC XY: 49 AN XY: 74460

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00871

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000466 Hom.: 0

Bravo AF: 0.000344

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spermatogenic failure 18;C4539798:Ciliary dyskinesia, primary, 37 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 23, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 24, 2021	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	14
DANN	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs375828810; hg19: chr3-52398835;