rs376327672

chr3-52349383-A-Cchr3-52349383-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015512.5(DNAH1):c.2489A>C(p.Asp830Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,613,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.36

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24704349).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH1	NM_015512.5	c.2489A>C	p.Asp830Ala	missense_variant	14/78	ENST00000420323.7
DNAH1	XM_017006129.2	c.2489A>C	p.Asp830Ala	missense_variant	15/80
DNAH1	XM_017006130.2	c.2489A>C	p.Asp830Ala	missense_variant	15/79
DNAH1	XM_017006131.2	c.2489A>C	p.Asp830Ala	missense_variant	15/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7	c.2489A>C	p.Asp830Ala	missense_variant	14/78	1	NM_015512.5	P1
DNAH1	ENST00000486752.5	n.2750A>C		non_coding_transcript_exon_variant	14/77	2
DNAH1	ENST00000497875.1	n.2654A>C		non_coding_transcript_exon_variant	15/21	2

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000602 AC: 15 AN: 249100 Hom.: 0 AF XY: 0.0000518 AC XY: 7 AN XY: 135176

Gnomad AFR exome AF: 0.000711

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1461624 Hom.: 0 Cov.: 34 AF XY: 0.0000261 AC XY: 19 AN XY: 727110

Gnomad4 AFR exome AF: 0.000627

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152234 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74370

Gnomad4 AFR AF: 0.000820

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000263 Hom.: 0

Bravo AF: 0.000234

ESP6500AA AF: 0.000691 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000660 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 09, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). ClinVar contains an entry for this variant (Variation ID: 582738). This variant has not been reported in the literature in individuals affected with DNAH1-related conditions. This variant is present in population databases (rs376327672, gnomAD 0.07%). This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 830 of the DNAH1 protein (p.Asp830Ala). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.36
Cadd	Uncertain	24
Dann	Uncertain	0.98
Eigen	Benign	0.087
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.11
Sift	Benign	0.42	T
Sift4G	Benign	0.33	T
Vest4		0.69
MVP		0.39
MPC		0.16
ClinPred		0.12	T
GERP RS		5.5
gMVP		0.61

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: rs376327672; hg19: chr3-52383399;