3-52375397-C-G

Position:

• chr3-52375397-C-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.7143C>G​(p.Ile2381Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0036 in 1,613,368 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (28 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0410

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=0.010921031).
• BP6: Variant 3-52375397-C-G is Benign according to our data. Variant chr3-52375397-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 478487.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-52375397-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00244 (372/152326) while in subpopulation SAS AF= 0.012 (58/4830). AF 95% confidence interval is 0.00954. There are 1 homozygotes in gnomad4. There are 199 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH1	NM_015512.5	c.7143C>G	p.Ile2381Met	missense_variant	45/78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2	c.7212C>G	p.Ile2404Met	missense_variant	47/80		XP_016861618.1
DNAH1	XM_017006130.2	c.7143C>G	p.Ile2381Met	missense_variant	46/79		XP_016861619.1
DNAH1	XM_017006131.2	c.7212C>G	p.Ile2404Met	missense_variant	47/79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7	c.7143C>G	p.Ile2381Met	missense_variant	45/78	1	NM_015512.5	ENSP00000401514	P1
DNAH1	ENST00000486752.5	n.7404C>G		non_coding_transcript_exon_variant	45/77	2

Frequencies

GnomAD3 genomes AF: 0.00245 AC: 373 AN: 152208 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0122

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00365

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00357 AC: 886 AN: 247844 Hom.: 5 AF XY: 0.00438 AC XY: 589 AN XY: 134480

Gnomad AFR exome AF: 0.000457

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.0148

Gnomad FIN exome AF: 0.000376

Gnomad NFE exome AF: 0.00319

Gnomad OTH exome AF: 0.00299

GnomAD4 exome AF: 0.00372 AC: 5429 AN: 1461042 Hom.: 28 Cov.: 31 AF XY: 0.00409 AC XY: 2974 AN XY: 726790

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.00139

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0147

Gnomad4 FIN exome AF: 0.000376

Gnomad4 NFE exome AF: 0.00349

Gnomad4 OTH exome AF: 0.00280

GnomAD4 genome AF: 0.00244 AC: 372 AN: 152326 Hom.: 1 Cov.: 32 AF XY: 0.00267 AC XY: 199 AN XY: 74492

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0120

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00365

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00303 Hom.: 1

Bravo AF: 0.00231

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000240 AC: 1

ESP6500EA AF: 0.00356 AC: 30

ExAC AF: 0.00379 AC: 458

EpiCase AF: 0.00245

EpiControl AF: 0.00321

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

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 08, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.71	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.27
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.083	T
Vest4		0.86
MVP		0.58
MPC		0.58
ClinPred		0.018	T
GERP RS		2.4
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs144580984; hg19: chr3-52409413;