chr3-52346727-G-A

Position:

• chr3-52346727-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_015512.5(DNAH1):​c.1912G>A​(p.Asp638Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00193 in 1,613,268 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (2 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.15

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0084910095).
• BP6: Variant 3-52346727-G-A is Benign according to our data. Variant chr3-52346727-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 478418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH1	NM_015512.5	c.1912G>A	p.Asp638Asn	missense_variant	11/78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2	c.1912G>A	p.Asp638Asn	missense_variant	12/80		XP_016861618.1
DNAH1	XM_017006130.2	c.1912G>A	p.Asp638Asn	missense_variant	12/79		XP_016861619.1
DNAH1	XM_017006131.2	c.1912G>A	p.Asp638Asn	missense_variant	12/79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7	c.1912G>A	p.Asp638Asn	missense_variant	11/78	1	NM_015512.5	ENSP00000401514	P1
DNAH1	ENST00000486752.5	n.2173G>A		non_coding_transcript_exon_variant	11/77	2
DNAH1	ENST00000497875.1	n.2077G>A		non_coding_transcript_exon_variant	12/21	2

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 218 AN: 152214 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00225

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00152 AC: 377 AN: 248004 Hom.: 0 AF XY: 0.00152 AC XY: 205 AN XY: 134652

Gnomad AFR exome AF: 0.000779

Gnomad AMR exome AF: 0.00134

Gnomad ASJ exome AF: 0.00808

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.000325

Gnomad NFE exome AF: 0.00194

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.00199 AC: 2900 AN: 1460936 Hom.: 2 Cov.: 32 AF XY: 0.00194 AC XY: 1410 AN XY: 726600

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.00128

Gnomad4 ASJ exome AF: 0.00823

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.000431

Gnomad4 NFE exome AF: 0.00216

Gnomad4 OTH exome AF: 0.00295

GnomAD4 genome AF: 0.00143 AC: 218 AN: 152332 Hom.: 1 Cov.: 33 AF XY: 0.00129 AC XY: 96 AN XY: 74486

Gnomad4 AFR AF: 0.000769

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00225

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00111 Hom.: 1

Bravo AF: 0.00144

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000232 AC: 1

ESP6500EA AF: 0.00258 AC: 22

ExAC AF: 0.00147 AC: 178

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00245

EpiControl AF: 0.00154

ClinVar

Significance: 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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2024

DNAH1: BP4 -

DNAH1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 15, 2019

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	0.076
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	13
DANN	Uncertain	0.98
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.0085	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.079
Sift	Benign	0.38	T
Sift4G	Benign	0.49	T
Vest4		0.29
MVP		0.20
MPC		0.12
ClinPred		0.0023	T
GERP RS		4.5
gMVP		0.18

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: rs201988957; hg19: chr3-52380743; COSMIC: COSV70231823;