chr3-52347849-A-G

Position:

• chr3-52347849-A-G

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.1981A>G​(p.Met661Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00556 in 1,599,060 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 0.0037 (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: 1.01

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=0.004538268).
• BP6: Variant 3-52347849-A-G is Benign according to our data. Variant chr3-52347849-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 478421.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 = 0.00374 (570/152270) while in subpopulation SAS AF= 0.0232 (112/4830). AF 95% confidence interval is 0.0197. There are 4 homozygotes in gnomad4. There are 289 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.1981A>G	p.Met661Val	missense_variant	12/78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2	c.1981A>G	p.Met661Val	missense_variant	13/80		XP_016861618.1
DNAH1	XM_017006130.2	c.1981A>G	p.Met661Val	missense_variant	13/79		XP_016861619.1
DNAH1	XM_017006131.2	c.1981A>G	p.Met661Val	missense_variant	13/79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7	c.1981A>G	p.Met661Val	missense_variant	12/78	1	NM_015512.5	ENSP00000401514	P1
DNAH1	ENST00000486752.5	n.2242A>G		non_coding_transcript_exon_variant	12/77	2
DNAH1	ENST00000497875.1	n.2146A>G		non_coding_transcript_exon_variant	13/21	2

Frequencies

GnomAD3 genomes AF: 0.00375 AC: 571 AN: 152152 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00443

Gnomad SAS AF: 0.0234

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00475

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00564 AC: 1286 AN: 227936 Hom.: 10 AF XY: 0.00667 AC XY: 823 AN XY: 123318

Gnomad AFR exome AF: 0.000886

Gnomad AMR exome AF: 0.00246

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00354

Gnomad SAS exome AF: 0.0233

Gnomad FIN exome AF: 0.00157

Gnomad NFE exome AF: 0.00417

Gnomad OTH exome AF: 0.00282

GnomAD4 exome AF: 0.00576 AC: 8328 AN: 1446790 Hom.: 65 Cov.: 31 AF XY: 0.00628 AC XY: 4510 AN XY: 717922

Gnomad4 AFR exome AF: 0.000663

Gnomad4 AMR exome AF: 0.00229

Gnomad4 ASJ exome AF: 0.00159

Gnomad4 EAS exome AF: 0.00371

Gnomad4 SAS exome AF: 0.0232

Gnomad4 FIN exome AF: 0.00150

Gnomad4 NFE exome AF: 0.00510

Gnomad4 OTH exome AF: 0.00569

GnomAD4 genome AF: 0.00374 AC: 570 AN: 152270 Hom.: 4 Cov.: 33 AF XY: 0.00388 AC XY: 289 AN XY: 74466

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00444

Gnomad4 SAS AF: 0.0232

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00474

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00387 Hom.: 6

Bravo AF: 0.00290

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000735 AC: 3

ESP6500EA AF: 0.00382 AC: 32

ExAC AF: 0.00577 AC: 697

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

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	0.048
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.4
DANN	Benign	0.30
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.066	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.12	N
REVEL	Benign	0.029
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.18
MVP		0.072
MPC		0.13
ClinPred		0.00059	T
GERP RS		3.1
gMVP		0.28

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: rs61734653; hg19: chr3-52381865;