rs202011102

Positions:

• chr3-52375363-A-C
• chr3-52375363-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_015512.5(DNAH1):​c.7109A>C​(p.Asp2370Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000998 in 1,613,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D2370D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.31

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.012574166).
• BP6: Variant 3-52375363-A-C is Benign according to our data. Variant chr3-52375363-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 478485.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH1	NM_015512.5	c.7109A>C	p.Asp2370Ala	missense_variant	45/78	ENST00000420323.7
DNAH1	XM_017006129.2	c.7178A>C	p.Asp2393Ala	missense_variant	47/80
DNAH1	XM_017006130.2	c.7109A>C	p.Asp2370Ala	missense_variant	46/79
DNAH1	XM_017006131.2	c.7178A>C	p.Asp2393Ala	missense_variant	47/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7	c.7109A>C	p.Asp2370Ala	missense_variant	45/78	1	NM_015512.5	P1
DNAH1	ENST00000486752.5	n.7370A>C		non_coding_transcript_exon_variant	45/77	2

Frequencies

GnomAD3 genomes AF: 0.000546 AC: 83 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00200

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: 0.000157 AC: 39 AN: 248466 Hom.: 0 AF XY: 0.000104 AC XY: 14 AN XY: 134826

Gnomad AFR exome AF: 0.00247

Gnomad AMR exome AF: 0.0000291

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: 0.0000534 AC: 78 AN: 1461380 Hom.: 0 Cov.: 31 AF XY: 0.0000385 AC XY: 28 AN XY: 726936

Gnomad4 AFR exome AF: 0.00212

Gnomad4 AMR exome AF: 0.0000224

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: 8.99e-7

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000545 AC: 83 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.000457 AC XY: 34 AN XY: 74434

Gnomad4 AFR AF: 0.00200

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: 0.000106 Hom.: 0

Bravo AF: 0.000589

ESP6500AA AF: 0.00213 AC: 9

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000239 AC: 29

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 23, 2022

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Mar 08, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	23
DANN	Uncertain	0.98
Eigen	Benign	-0.070
Eigen_PC	Benign	0.089
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.075
Sift	Benign	0.21	T
Sift4G	Benign	0.36	T
Vest4		0.56
MVP		0.35
MPC		0.16
ClinPred		0.037	T
GERP RS		5.7
gMVP		0.53

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: rs202011102; hg19: chr3-52409379;