3-52396681-C-T

Position:

• chr3-52396681-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_015512.5(DNAH1):​c.11494C>T​(p.Arg3832Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00346 in 1,613,720 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3832H) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0033 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (18 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.65

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010175705).
• BP6: Variant 3-52396681-C-T is Benign according to our data. Variant chr3-52396681-C-T is described in ClinVar as [Benign]. Clinvar id is 478400.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00331 (504/152210) while in subpopulation NFE AF= 0.00329 (224/68014). AF 95% confidence interval is 0.00294. There are 3 homozygotes in gnomad4. There are 308 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH1	NM_015512.5	c.11494C>T	p.Arg3832Cys	missense_variant	72/78	ENST00000420323.7
DNAH1	XM_017006129.2	c.11563C>T	p.Arg3855Cys	missense_variant	74/80
DNAH1	XM_017006130.2	c.11494C>T	p.Arg3832Cys	missense_variant	73/79
DNAH1	XM_017006131.2	c.11437C>T	p.Arg3813Cys	missense_variant	73/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7	c.11494C>T	p.Arg3832Cys	missense_variant	72/78	1	NM_015512.5	P1
DNAH1	ENST00000486752.5	n.11951C>T		non_coding_transcript_exon_variant	71/77	2
DNAH1	ENST00000488988.5	n.3280C>T		non_coding_transcript_exon_variant	19/25	2
DNAH1	ENST00000490713.5	c.2194C>T	p.Arg732Cys	missense_variant, NMD_transcript_variant	15/20	5

Frequencies

GnomAD3 genomes AF: 0.00332 AC: 505 AN: 152092 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000749

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0218

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00329

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00393 AC: 978 AN: 249098 Hom.: 7 AF XY: 0.00383 AC XY: 517 AN XY: 135144

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.000464

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.00229

Gnomad FIN exome AF: 0.0233

Gnomad NFE exome AF: 0.00326

Gnomad OTH exome AF: 0.00248

GnomAD4 exome AF: 0.00348 AC: 5079 AN: 1461510 Hom.: 18 Cov.: 34 AF XY: 0.00341 AC XY: 2480 AN XY: 727018

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.000648

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000277

Gnomad4 SAS exome AF: 0.00203

Gnomad4 FIN exome AF: 0.0206

Gnomad4 NFE exome AF: 0.00321

Gnomad4 OTH exome AF: 0.00297

GnomAD4 genome AF: 0.00331 AC: 504 AN: 152210 Hom.: 3 Cov.: 32 AF XY: 0.00414 AC XY: 308 AN XY: 74414

Gnomad4 AFR AF: 0.000746

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.0218

Gnomad4 NFE AF: 0.00329

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00280 Hom.: 2

Bravo AF: 0.00170

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000247 AC: 1

ESP6500EA AF: 0.00311 AC: 26

ExAC AF: 0.00343 AC: 415

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00245

EpiControl AF: 0.00302

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 16, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	29
DANN	Uncertain	0.99
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.010	T
MutationTaster	Benign	1.0	N
Sift4G	Pathogenic	0.0	D
Vest4		0.73
MVP		0.36
ClinPred		0.011	T
GERP RS		3.5
gMVP		0.84

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: rs200962458; hg19: chr3-52430697;