rs187636110

chr3-52348985-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015512.5(DNAH1):c.2204G>A(p.Ser735Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00418 in 1,613,464 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0043 (28 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.328

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009891301).
• BP6: Variant 3-52348985-G-A is Benign according to our data. Variant chr3-52348985-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 478424.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 = 0.00319 (486/152352) while in subpopulation NFE AF= 0.00491 (334/68038). AF 95% confidence interval is 0.00448. There are 1 homozygotes in gnomad4. There are 222 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH1	NM_015512.5	c.2204G>A	p.Ser735Asn	missense_variant	13/78	ENST00000420323.7
DNAH1	XM_017006129.2	c.2204G>A	p.Ser735Asn	missense_variant	14/80
DNAH1	XM_017006130.2	c.2204G>A	p.Ser735Asn	missense_variant	14/79
DNAH1	XM_017006131.2	c.2204G>A	p.Ser735Asn	missense_variant	14/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7	c.2204G>A	p.Ser735Asn	missense_variant	13/78	1	NM_015512.5	P1
DNAH1	ENST00000486752.5	n.2465G>A		non_coding_transcript_exon_variant	13/77	2
DNAH1	ENST00000497875.1	n.2369G>A		non_coding_transcript_exon_variant	14/21	2

Frequencies

GnomAD3 genomes AF: 0.00319 AC: 486 AN: 152234 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000675

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0101

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00491

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00413 AC: 1026 AN: 248688 Hom.: 10 AF XY: 0.00396 AC XY: 534 AN XY: 134944

Gnomad AFR exome AF: 0.000645

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000784

Gnomad FIN exome AF: 0.0110

Gnomad NFE exome AF: 0.00647

Gnomad OTH exome AF: 0.00347

GnomAD4 exome AF: 0.00428 AC: 6251 AN: 1461112 Hom.: 28 Cov.: 33 AF XY: 0.00428 AC XY: 3114 AN XY: 726836

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.000612

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000499

Gnomad4 FIN exome AF: 0.0113

Gnomad4 NFE exome AF: 0.00482

Gnomad4 OTH exome AF: 0.00343

GnomAD4 genome AF: 0.00319 AC: 486 AN: 152352 Hom.: 1 Cov.: 33 AF XY: 0.00298 AC XY: 222 AN XY: 74506

Gnomad4 AFR AF: 0.000673

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0101

Gnomad4 NFE AF: 0.00491

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00406 Hom.: 0

Bravo AF: 0.00234

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000921 AC: 4

ESP6500EA AF: 0.00608 AC: 52

ExAC AF: 0.00489 AC: 593

EpiCase AF: 0.00305

EpiControl AF: 0.00367

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	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	DNAH1: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 21, 2023	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	0.23
Dann	Benign	0.28
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.43	T
MetaRNN	Benign	0.0099	T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.051
Sift	Benign	0.52	T
Sift4G	Benign	0.51	T
Vest4		0.22
MVP		0.072
MPC		0.12
ClinPred		0.00079	T
GERP RS		2.8
gMVP		0.18

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: rs187636110; hg19: chr3-52383001; COSMIC: COSV70229834;