rs199996069

Positions:

• chr3-52347837-C-G
• chr3-52347837-C-T

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.1969C>G​(p.Pro657Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000603 in 1,593,138 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00063 (17 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.47

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]

DNAH1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010119915).
• BP6: Variant 3-52347837-C-G is Benign according to our data. Variant chr3-52347837-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 544643.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000322 (49/152316) while in subpopulation SAS AF= 0.00911 (44/4828). AF 95% confidence interval is 0.00698. There are 0 homozygotes in gnomad4. There are 30 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH1	NM_015512.5	c.1969C>G	p.Pro657Ala	missense_variant	12/78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2	c.1969C>G	p.Pro657Ala	missense_variant	13/80		XP_016861618.1
DNAH1	XM_017006130.2	c.1969C>G	p.Pro657Ala	missense_variant	13/79		XP_016861619.1
DNAH1	XM_017006131.2	c.1969C>G	p.Pro657Ala	missense_variant	13/79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7	c.1969C>G	p.Pro657Ala	missense_variant	12/78	1	NM_015512.5	ENSP00000401514.2
DNAH1	ENST00000486752.5	n.2230C>G		non_coding_transcript_exon_variant	12/77	2
DNAH1	ENST00000497875.1	n.2134C>G		non_coding_transcript_exon_variant	13/21	2

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00931

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00126 AC: 282 AN: 223032 Hom.: 3 AF XY: 0.00162 AC XY: 195 AN XY: 120604

Gnomad AFR exome AF: 0.0000754

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0102

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000100

Gnomad OTH exome AF: 0.000896

GnomAD4 exome AF: 0.000633 AC: 912 AN: 1440822 Hom.: 17 Cov.: 31 AF XY: 0.000883 AC XY: 631 AN XY: 714210

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0101

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000545

Gnomad4 OTH exome AF: 0.000874

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152316 Hom.: 0 Cov.: 33 AF XY: 0.000403 AC XY: 30 AN XY: 74486

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00911

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000793

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000243 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00144 AC: 174

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Significance: Benign/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	Fulgent Genetics, Fulgent Genetics	Jan 17, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 10, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	18
DANN	Benign	0.97
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.061
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Benign	0.17
Sift	Benign	0.083	T
Sift4G	Benign	0.097	T
Vest4		0.45
MVP		0.25
MPC		0.13
ClinPred		0.13	T
GERP RS		4.1
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199996069; hg19: chr3-52381853;