rs61749019

Positions:

• chr3-52383975-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.8266G>A​(p.Val2756Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00559 in 1,611,248 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0058 (65 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.24

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=0.004161179).
• BP6: Variant 3-52383975-G-A is Benign according to our data. Variant chr3-52383975-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 478499.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 = 0.00377 (574/152302) while in subpopulation SAS AF= 0.0233 (112/4814). AF 95% confidence interval is 0.0198. There are 4 homozygotes in gnomad4. There are 291 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH1	NM_015512.5	c.8266G>A	p.Val2756Met	missense_variant	52/78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2	c.8335G>A	p.Val2779Met	missense_variant	54/80		XP_016861618.1
DNAH1	XM_017006130.2	c.8266G>A	p.Val2756Met	missense_variant	53/79		XP_016861619.1
DNAH1	XM_017006131.2	c.8335G>A	p.Val2779Met	missense_variant	54/79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7	c.8266G>A	p.Val2756Met	missense_variant	52/78	1	NM_015512.5	ENSP00000401514	P1
DNAH1	ENST00000486752.5	n.8527G>A		non_coding_transcript_exon_variant	52/77	2

Frequencies

GnomAD3 genomes AF: 0.00378 AC: 575 AN: 152184 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00442

Gnomad SAS AF: 0.0235

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00476

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00572 AC: 1391 AN: 243172 Hom.: 10 AF XY: 0.00681 AC XY: 899 AN XY: 131928

Gnomad AFR exome AF: 0.000940

Gnomad AMR exome AF: 0.00251

Gnomad ASJ exome AF: 0.00152

Gnomad EAS exome AF: 0.00375

Gnomad SAS exome AF: 0.0234

Gnomad FIN exome AF: 0.00161

Gnomad NFE exome AF: 0.00421

Gnomad OTH exome AF: 0.00303

GnomAD4 exome AF: 0.00578 AC: 8436 AN: 1458946 Hom.: 65 Cov.: 31 AF XY: 0.00632 AC XY: 4587 AN XY: 725458

Gnomad4 AFR exome AF: 0.000688

Gnomad4 AMR exome AF: 0.00232

Gnomad4 ASJ exome AF: 0.00157

Gnomad4 EAS exome AF: 0.00381

Gnomad4 SAS exome AF: 0.0232

Gnomad4 FIN exome AF: 0.00152

Gnomad4 NFE exome AF: 0.00511

Gnomad4 OTH exome AF: 0.00566

GnomAD4 genome AF: 0.00377 AC: 574 AN: 152302 Hom.: 4 Cov.: 33 AF XY: 0.00391 AC XY: 291 AN XY: 74476

Gnomad4 AFR AF: 0.000938

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00443

Gnomad4 SAS AF: 0.0233

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00475

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.00392 Hom.: 6

Bravo AF: 0.00293

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000524 AC: 2

ESP6500EA AF: 0.00365 AC: 30

ExAC AF: 0.00600 AC: 725

Asia WGS AF: 0.00837 AC: 29 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 25, 2023	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	15
DANN	Benign	0.95
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.034	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.087
Sift	Benign	0.34	T
Sift4G	Benign	0.28	T
Vest4		0.14
MVP		0.17
MPC		0.13
ClinPred		0.0024	T
GERP RS		4.4
gMVP		0.14

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: rs61749019; hg19: chr3-52417991;