3-52360327-A-G

Position:

• chr3-52360327-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.4588A>G​(p.Asn1530Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00154 in 1,613,788 control chromosomes in the GnomAD database, including 47 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 0.0082 (26 hom., cov: 33)
  • Exomes 𝑓: 0.00085 (21 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.294

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=0.0020741224).
• BP6: Variant 3-52360327-A-G is Benign according to our data. Variant chr3-52360327-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 478451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00825 (1256/152314) while in subpopulation AFR AF= 0.0289 (1200/41554). AF 95% confidence interval is 0.0275. There are 26 homozygotes in gnomad4. There are 582 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH1	NM_015512.5	c.4588A>G	p.Asn1530Asp	missense_variant	28/78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2	c.4588A>G	p.Asn1530Asp	missense_variant	29/80		XP_016861618.1
DNAH1	XM_017006130.2	c.4588A>G	p.Asn1530Asp	missense_variant	29/79		XP_016861619.1
DNAH1	XM_017006131.2	c.4588A>G	p.Asn1530Asp	missense_variant	29/79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7	c.4588A>G	p.Asn1530Asp	missense_variant	28/78	1	NM_015512.5	ENSP00000401514	P1
DNAH1	ENST00000486752.5	n.4849A>G		non_coding_transcript_exon_variant	28/77	2

Frequencies

GnomAD3 genomes AF: 0.00825 AC: 1256 AN: 152196 Hom.: 26 Cov.: 33

Gnomad AFR AF: 0.0290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00163

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00209 AC: 521 AN: 248912 Hom.: 12 AF XY: 0.00156 AC XY: 211 AN XY: 135048

Gnomad AFR exome AF: 0.0310

Gnomad AMR exome AF: 0.000841

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000709

Gnomad OTH exome AF: 0.000662

GnomAD4 exome AF: 0.000846 AC: 1237 AN: 1461474 Hom.: 21 Cov.: 31 AF XY: 0.000733 AC XY: 533 AN XY: 727012

Gnomad4 AFR exome AF: 0.0307

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000387

Gnomad4 OTH exome AF: 0.00186

GnomAD4 genome AF: 0.00825 AC: 1256 AN: 152314 Hom.: 26 Cov.: 33 AF XY: 0.00781 AC XY: 582 AN XY: 74494

Gnomad4 AFR AF: 0.0289

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00138 Hom.: 7

Bravo AF: 0.00990

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0316 AC: 133

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.00271 AC: 328

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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 14, 2018	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.5
DANN	Benign	0.25
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	1.7	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.24
MVP		0.085
MPC		0.14
ClinPred		0.00060	T
GERP RS		-5.8
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs74498533; hg19: chr3-52394343;