rs200850423

Positions:

• chr3-52394603-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The NM_015512.5(DNAH1):​c.10765G>A​(p.Asp3589Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000076 in 1,605,248 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000077 (1 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.21

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 -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03445351).
• BP6: Variant 3-52394603-G-A is Benign according to our data. Variant chr3-52394603-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 478388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH1	NM_015512.5	c.10765G>A	p.Asp3589Asn	missense_variant	67/78	ENST00000420323.7
DNAH1	XM_017006129.2	c.10834G>A	p.Asp3612Asn	missense_variant	69/80
DNAH1	XM_017006130.2	c.10765G>A	p.Asp3589Asn	missense_variant	68/79
DNAH1	XM_017006131.2	c.10708G>A	p.Asp3570Asn	missense_variant	68/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7	c.10765G>A	p.Asp3589Asn	missense_variant	67/78	1	NM_015512.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

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: 0.000479

GnomAD3 exomes AF: 0.000351 AC: 85 AN: 242370 Hom.: 1 AF XY: 0.000259 AC XY: 34 AN XY: 131240

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00245

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: 0.00000912

Gnomad OTH exome AF: 0.000171

GnomAD4 exome AF: 0.0000771 AC: 112 AN: 1452936 Hom.: 1 Cov.: 32 AF XY: 0.0000610 AC XY: 44 AN XY: 721718

Gnomad4 AFR exome AF: 0.0000899

Gnomad4 AMR exome AF: 0.00217

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000362

Gnomad4 OTH exome AF: 0.000117

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74478

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000588

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: 0.000474

Alfa AF: 0.000136 Hom.: 0

Bravo AF: 0.000170

ExAC AF: 0.000248 AC: 30

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

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	Invitae	Oct 06, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 05, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	23
DANN	Uncertain	1.0
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.92	D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.21
Sift	Benign	0.39	T
Sift4G	Benign	0.46	T
Vest4		0.54
MVP		0.54
MPC		0.15
ClinPred		0.049	T
GERP RS		5.2
gMVP		0.58

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: rs200850423; hg19: chr3-52428619; COSMIC: COSV101327457; COSMIC: COSV101327457;