chr3-52378778-G-A

Position:

• chr3-52378778-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.7375G>A​(p.Glu2459Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00187 in 1,613,500 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0018 (14 hom.)
• Consequence: DNAH1 NM_015512.5 missense, splice_region
• Scores: Splicing: ADA: 0.0001947
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.40

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=0.008411378).
• BP6: Variant 3-52378778-G-A is Benign according to our data. Variant chr3-52378778-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 544656.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 = 0.00256 (390/152278) while in subpopulation NFE AF= 0.00394 (268/68012). AF 95% confidence interval is 0.00355. There are 3 homozygotes in gnomad4. There are 203 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH1	NM_015512.5	c.7375G>A	p.Glu2459Lys	missense_variant, splice_region_variant	47/78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2	c.7444G>A	p.Glu2482Lys	missense_variant, splice_region_variant	49/80		XP_016861618.1
DNAH1	XM_017006130.2	c.7375G>A	p.Glu2459Lys	missense_variant, splice_region_variant	48/79		XP_016861619.1
DNAH1	XM_017006131.2	c.7444G>A	p.Glu2482Lys	missense_variant, splice_region_variant	49/79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7	c.7375G>A	p.Glu2459Lys	missense_variant, splice_region_variant	47/78	1	NM_015512.5	ENSP00000401514	P1
DNAH1	ENST00000486752.5	n.7636G>A		splice_region_variant, non_coding_transcript_exon_variant	47/77	2

Frequencies

GnomAD3 genomes AF: 0.00256 AC: 390 AN: 152160 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0102

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00394

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00256 AC: 638 AN: 248786 Hom.: 3 AF XY: 0.00249 AC XY: 336 AN XY: 134982

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00299

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.0105

Gnomad NFE exome AF: 0.00326

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00180 AC: 2634 AN: 1461222 Hom.: 14 Cov.: 31 AF XY: 0.00193 AC XY: 1404 AN XY: 726870

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00283

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00904

Gnomad4 NFE exome AF: 0.00178

Gnomad4 OTH exome AF: 0.00156

GnomAD4 genome AF: 0.00256 AC: 390 AN: 152278 Hom.: 3 Cov.: 31 AF XY: 0.00273 AC XY: 203 AN XY: 74452

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0102

Gnomad4 NFE AF: 0.00394

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00303 Hom.: 3

Bravo AF: 0.00144

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00258 AC: 22

ExAC AF: 0.00254 AC: 308

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00300

EpiControl AF: 0.00166

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:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2024

DNAH1: BP4, BS2 -

DNAH1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 03, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	21
DANN	Benign	0.52
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0084	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.66	D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.025
Sift	Benign	0.64	T
Sift4G	Benign	0.84	T
Vest4		0.41
MVP		0.23
MPC		0.14
ClinPred		0.014	T
GERP RS		4.2
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00019
dbscSNV1_RF	Benign	0.038
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: rs201064587; hg19: chr3-52412794;