12-123789927-A-G

Position:

• chr12-123789927-A-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.1621A>G​(p.Ile541Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.685 in 1,609,552 control chromosomes in the GnomAD database, including 382,337 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (42753 hom., cov: 32)
  • Exomes 𝑓: 0.68 (339584 hom.)
• Consequence: DNAH10 NM_001372106.1 missense, splice_region
• Scores: Splicing: ADA: 0.00001317
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.43

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]

DNAH10 (HGNC:):

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=7.68572E-7).
• BP6: Variant 12-123789927-A-G is Benign according to our data. Variant chr12-123789927-A-G is described in ClinVar as [Benign]. Clinvar id is 402614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-123789927-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.973 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH10	NM_001372106.1	c.1621A>G	p.Ile541Val	missense_variant, splice_region_variant	11/79	ENST00000673944.1	NP_001359035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH10	ENST00000673944.1	c.1621A>G	p.Ile541Val	missense_variant, splice_region_variant	11/79		NM_001372106.1	ENSP00000501095.1

Frequencies

GnomAD3 genomes AF: 0.743 AC: 112916 AN: 151980 Hom.: 42692 Cov.: 32

Gnomad AFR AF: 0.849

Gnomad AMI AF: 0.610

Gnomad AMR AF: 0.771

Gnomad ASJ AF: 0.729

Gnomad EAS AF: 0.996

Gnomad SAS AF: 0.752

Gnomad FIN AF: 0.684

Gnomad MID AF: 0.693

Gnomad NFE AF: 0.664

Gnomad OTH AF: 0.748

GnomAD3 exomes AF: 0.728 AC: 181347 AN: 249100 Hom.: 67240 AF XY: 0.723 AC XY: 97242 AN XY: 134526

Gnomad AFR exome AF: 0.847

Gnomad AMR exome AF: 0.765

Gnomad ASJ exome AF: 0.731

Gnomad EAS exome AF: 0.999

Gnomad SAS exome AF: 0.727

Gnomad FIN exome AF: 0.674

Gnomad NFE exome AF: 0.667

Gnomad OTH exome AF: 0.712

GnomAD4 exome AF: 0.679 AC: 989162 AN: 1457454 Hom.: 339584 Cov.: 38 AF XY: 0.680 AC XY: 492754 AN XY: 724488

Gnomad4 AFR exome AF: 0.851

Gnomad4 AMR exome AF: 0.767

Gnomad4 ASJ exome AF: 0.732

Gnomad4 EAS exome AF: 0.999

Gnomad4 SAS exome AF: 0.724

Gnomad4 FIN exome AF: 0.685

Gnomad4 NFE exome AF: 0.652

Gnomad4 OTH exome AF: 0.702

GnomAD4 genome AF: 0.743 AC: 113033 AN: 152098 Hom.: 42753 Cov.: 32 AF XY: 0.747 AC XY: 55491 AN XY: 74328

Gnomad4 AFR AF: 0.849

Gnomad4 AMR AF: 0.772

Gnomad4 ASJ AF: 0.729

Gnomad4 EAS AF: 0.996

Gnomad4 SAS AF: 0.753

Gnomad4 FIN AF: 0.684

Gnomad4 NFE AF: 0.664

Gnomad4 OTH AF: 0.751

Alfa AF: 0.687 Hom.: 60286

Bravo AF: 0.754

TwinsUK AF: 0.649 AC: 2405

ALSPAC AF: 0.646 AC: 2490

ESP6500AA AF: 0.850 AC: 3743

ESP6500EA AF: 0.670 AC: 5759

ExAC AF: 0.729 AC: 88467

Asia WGS AF: 0.883 AC: 3068 AN: 3478

EpiCase AF: 0.662

EpiControl AF: 0.675

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	0.063
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	17
DANN	Benign	0.32
DEOGEN2	Benign	0.0045	.;T;T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.16	T;T;T
MetaRNN	Benign	7.7e-7	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.9	.;.;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.11	N;.;.
REVEL	Benign	0.13
Sift	Benign	0.53	T;.;.
Sift4G	Benign	1.0	.;T;.
Polyphen		0.0	.;.;B
Vest4		0.021
MPC		0.12
ClinPred		0.0055	T
GERP RS		5.2
Varity_R		0.071
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000013
dbscSNV1_RF	Benign	0.0040
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: rs10846559; hg19: chr12-124274474;