12-123928562-T-C

Position:

• chr12-123928562-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_001372106.1(DNAH10):​c.12281T>C​(p.Ile4094Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00195 in 1,606,676 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (11 hom.)
• Consequence: DNAH10 NM_001372106.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 7.95

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]

DNAH10OS (HGNC:37121): (dynein axonemal heavy chain 10 opposite strand)

CCDC92 (HGNC:29563): (coiled-coil domain containing 92) Enables identical protein binding activity. Located in centriole; centrosome; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -8 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=0.01565805).
• BP6: Variant 12-123928562-T-C is Benign according to our data. Variant chr12-123928562-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 711074.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr12-123928562-T-C is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH10	NM_001372106.1	c.12281T>C	p.Ile4094Thr	missense_variant	70/79	ENST00000673944.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH10	ENST00000673944.1	c.12281T>C	p.Ile4094Thr	missense_variant	70/79		NM_001372106.1	P1
DNAH10OS	ENST00000514254.3	n.2902A>G		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.00130 AC: 198 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.000719

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00188

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00186 AC: 436 AN: 233974 Hom.: 1 AF XY: 0.00193 AC XY: 246 AN XY: 127140

Gnomad AFR exome AF: 0.000147

Gnomad AMR exome AF: 0.00111

Gnomad ASJ exome AF: 0.000208

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00242

Gnomad FIN exome AF: 0.00318

Gnomad NFE exome AF: 0.00239

Gnomad OTH exome AF: 0.00139

GnomAD4 exome AF: 0.00202 AC: 2942 AN: 1454366 Hom.: 11 Cov.: 31 AF XY: 0.00203 AC XY: 1467 AN XY: 722720

Gnomad4 AFR exome AF: 0.000240

Gnomad4 AMR exome AF: 0.00107

Gnomad4 ASJ exome AF: 0.0000772

Gnomad4 EAS exome AF: 0.0000507

Gnomad4 SAS exome AF: 0.00276

Gnomad4 FIN exome AF: 0.00324

Gnomad4 NFE exome AF: 0.00215

Gnomad4 OTH exome AF: 0.00156

GnomAD4 genome AF: 0.00130 AC: 198 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.00133 AC XY: 99 AN XY: 74486

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.000718

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00245

Gnomad4 NFE AF: 0.00188

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00152 Hom.: 2

Bravo AF: 0.00103

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000264 AC: 1

ESP6500EA AF: 0.00134 AC: 11

ExAC AF: 0.00213 AC: 257

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 12, 2017	- -

DNAH10-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 15, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.021	.;T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.016	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.8	.;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.72	T
REVEL	Uncertain	0.58
Polyphen		1.0	.;D
MVP		0.35
MPC		0.71
ClinPred		0.061	T
GERP RS		5.7
Varity_R		0.82
gMVP		0.49

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: rs182918679; hg19: chr12-124413109;