12-123841430-T-G

Variant names:

• chr12-123841430-T-G
• rs4930729
• NM_001372106.1:c.5245T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. 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. 14/19 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
• Publications: 30 publications found

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 Gene-Disease associations (from GenCC):

• spermatogenic failure 56

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• 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 VariationId is 402615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.946 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001372106.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH10	NM_001372106.1	MANE Select	c.5245T>G	p.Leu1749Val	missense	Exon 30 of 79	NP_001359035.1
	DNAH10	NM_207437.3		c.4891T>G	p.Leu1631Val	missense	Exon 29 of 78	NP_997320.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH10	ENST00000673944.1	MANE Select	c.5245T>G	p.Leu1749Val	missense	Exon 30 of 79	ENSP00000501095.1
	DNAH10	ENST00000409039.8	TSL:5	c.5074T>G	p.Leu1692Val	missense	Exon 29 of 78	ENSP00000386770.4
	DNAH10	ENST00000638045.1	TSL:5	c.4891T>G	p.Leu1631Val	missense	Exon 29 of 78	ENSP00000489675.1

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

GnomAD2 exomes AF: 0.833 AC: 207577 AN: 249270 AF XY: 0.829

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 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

African (AFR) AF: 0.961 AC: 32159 AN: 33480

American (AMR) AF: 0.835 AC: 37332 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.916 AC: 23939 AN: 26136

East Asian (EAS) AF: 0.582 AC: 23094 AN: 39700

South Asian (SAS) AF: 0.721 AC: 62152 AN: 86258

European-Finnish (FIN) AF: 0.886 AC: 47292 AN: 53400

Middle Eastern (MID) AF: 0.874 AC: 5043 AN: 5768

European-Non Finnish (NFE) AF: 0.890 AC: 989037 AN: 1111864

Other (OTH) AF: 0.862 AC: 52043 AN: 60374

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

African (AFR) AF: 0.954 AC: 39619 AN: 41548

American (AMR) AF: 0.852 AC: 13038 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.919 AC: 3190 AN: 3472

East Asian (EAS) AF: 0.531 AC: 2741 AN: 5160

South Asian (SAS) AF: 0.702 AC: 3387 AN: 4824

European-Finnish (FIN) AF: 0.886 AC: 9390 AN: 10594

Middle Eastern (MID) AF: 0.874 AC: 257 AN: 294

European-Non Finnish (NFE) AF: 0.886 AC: 60263 AN: 68016

Other (OTH) AF: 0.873 AC: 1841 AN: 2110

Alfa AF: 0.880 Hom.: 260607

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0000015	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	-2.4	N
PhyloP100		-0.28
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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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