12-123841430-T-G

Position:

• chr12-123841430-T-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001372106.1(DNAH10):​c.5245T>G​(p.Leu1749Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.872 in 1,613,928 control chromosomes in the GnomAD database, including 617,078 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.88 (60006 hom., cov: 32)
  • Exomes 𝑓: 0.87 (557072 hom.)
• Consequence: DNAH10 NM_001372106.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.283

Genes affected

DNAH10 (HGNC:2941): (dynein axonemal heavy chain 10) Dyneins are microtubule-associated motor protein complexes composed of several heavy, light, and intermediate chains. The axonemal dyneins, found in cilia and flagella, are components of the outer and inner dynein arms attached to the peripheral microtubule doublets. DNAH10 is an inner arm dynein heavy chain (Maiti et al., 2000 [PubMed 11175280]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DNAH10. . Gene score misZ 1.5457 (greater than the threshold 3.09). Trascript score misZ 3.4903 (greater than threshold 3.09). GenCC has associacion of gene with spermatogenic failure 56.
• BP4: Computational evidence support a benign effect (MetaRNN=1.505661E-6).
• BP6: Variant 12-123841430-T-G is Benign according to our data. Variant chr12-123841430-T-G is described in ClinVar as [Benign]. Clinvar id is 402615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-123841430-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.946 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH10	NM_001372106.1	c.5245T>G	p.Leu1749Val	missense_variant	30/79	ENST00000673944.1	NP_001359035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH10	ENST00000673944.1	c.5245T>G	p.Leu1749Val	missense_variant	30/79		NM_001372106.1	ENSP00000501095	P1
DNAH10	ENST00000409039.8	c.5074T>G	p.Leu1692Val	missense_variant	29/78	5		ENSP00000386770
DNAH10	ENST00000638045.1	c.4891T>G	p.Leu1631Val	missense_variant	29/78	5		ENSP00000489675
DNAH10	ENST00000497783.3	c.433T>G	p.Leu145Val	missense_variant, NMD_transcript_variant	3/21	2		ENSP00000444761

Frequencies

GnomAD3 genomes AF: 0.884 AC: 134426 AN: 152106 Hom.: 59955 Cov.: 32

Gnomad AFR AF: 0.953

Gnomad AMI AF: 0.882

Gnomad AMR AF: 0.853

Gnomad ASJ AF: 0.919

Gnomad EAS AF: 0.531

Gnomad SAS AF: 0.702

Gnomad FIN AF: 0.886

Gnomad MID AF: 0.867

Gnomad NFE AF: 0.886

Gnomad OTH AF: 0.882

GnomAD3 exomes AF: 0.833 AC: 207577 AN: 249270 Hom.: 88180 AF XY: 0.829 AC XY: 112092 AN XY: 135226

Gnomad AFR exome AF: 0.958

Gnomad AMR exome AF: 0.832

Gnomad ASJ exome AF: 0.912

Gnomad EAS exome AF: 0.495

Gnomad SAS exome AF: 0.715

Gnomad FIN exome AF: 0.880

Gnomad NFE exome AF: 0.884

Gnomad OTH exome AF: 0.858

GnomAD4 exome AF: 0.870 AC: 1272091 AN: 1461704 Hom.: 557072 Cov.: 78 AF XY: 0.866 AC XY: 629631 AN XY: 727136

Gnomad4 AFR exome AF: 0.961

Gnomad4 AMR exome AF: 0.835

Gnomad4 ASJ exome AF: 0.916

Gnomad4 EAS exome AF: 0.582

Gnomad4 SAS exome AF: 0.721

Gnomad4 FIN exome AF: 0.886

Gnomad4 NFE exome AF: 0.890

Gnomad4 OTH exome AF: 0.862

GnomAD4 genome AF: 0.884 AC: 134530 AN: 152224 Hom.: 60006 Cov.: 32 AF XY: 0.878 AC XY: 65318 AN XY: 74424

Gnomad4 AFR AF: 0.954

Gnomad4 AMR AF: 0.852

Gnomad4 ASJ AF: 0.919

Gnomad4 EAS AF: 0.531

Gnomad4 SAS AF: 0.702

Gnomad4 FIN AF: 0.886

Gnomad4 NFE AF: 0.886

Gnomad4 OTH AF: 0.873

Alfa AF: 0.878 Hom.: 142261

Bravo AF: 0.889

TwinsUK AF: 0.891 AC: 3302

ALSPAC AF: 0.882 AC: 3399

ESP6500AA AF: 0.955 AC: 3842

ESP6500EA AF: 0.899 AC: 7491

ExAC AF: 0.834 AC: 100847

Asia WGS AF: 0.644 AC: 2243 AN: 3478

EpiCase AF: 0.888

EpiControl AF: 0.891

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.022
DANN	Benign	0.11
DEOGEN2	Benign	0.022	.;T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.0071	N
LIST_S2	Benign	0.025	T;T
MetaRNN	Benign	0.0000015	T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	-2.4	.;N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.26	T
REVEL	Benign	0.22
Polyphen		0.0	.;B
MPC		0.15
ClinPred		0.0074	T
GERP RS		-5.3
Varity_R		0.061
gMVP		0.15

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: rs4930729; hg19: chr12-124325977; COSMIC: COSV68994568;