12-123781140-T-C

Position:

• chr12-123781140-T-C

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.682T>C​(p.Ser228Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.631 in 1,613,600 control chromosomes in the GnomAD database, including 325,110 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 0.63 (30974 hom., cov: 30)
  • Exomes 𝑓: 0.63 (294136 hom.)
• Consequence: DNAH10 NM_001372106.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.47

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]

LOC105370044 (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=1.1367255E-6).
• BP6: Variant 12-123781140-T-C is Benign according to our data. Variant chr12-123781140-T-C is described in ClinVar as [Benign]. Clinvar id is 402611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-123781140-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.922 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH10	NM_001372106.1	c.682T>C	p.Ser228Pro	missense_variant	6/79	ENST00000673944.1	NP_001359035.1
LOC105370044	XR_945481.4	n.495+7353A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH10	ENST00000673944.1	c.682T>C	p.Ser228Pro	missense_variant	6/79		NM_001372106.1	ENSP00000501095	P1

Frequencies

GnomAD3 genomes AF: 0.634 AC: 96171 AN: 151764 Hom.: 30940 Cov.: 30

Gnomad AFR AF: 0.565

Gnomad AMI AF: 0.593

Gnomad AMR AF: 0.692

Gnomad ASJ AF: 0.685

Gnomad EAS AF: 0.945

Gnomad SAS AF: 0.702

Gnomad FIN AF: 0.670

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.626

Gnomad OTH AF: 0.644

GnomAD3 exomes AF: 0.667 AC: 167460 AN: 251206 Hom.: 56911 AF XY: 0.666 AC XY: 90484 AN XY: 135810

Gnomad AFR exome AF: 0.556

Gnomad AMR exome AF: 0.696

Gnomad ASJ exome AF: 0.684

Gnomad EAS exome AF: 0.949

Gnomad SAS exome AF: 0.675

Gnomad FIN exome AF: 0.659

Gnomad NFE exome AF: 0.626

Gnomad OTH exome AF: 0.652

GnomAD4 exome AF: 0.631 AC: 922399 AN: 1461720 Hom.: 294136 Cov.: 62 AF XY: 0.633 AC XY: 460440 AN XY: 727162

Gnomad4 AFR exome AF: 0.551

Gnomad4 AMR exome AF: 0.698

Gnomad4 ASJ exome AF: 0.686

Gnomad4 EAS exome AF: 0.950

Gnomad4 SAS exome AF: 0.671

Gnomad4 FIN exome AF: 0.667

Gnomad4 NFE exome AF: 0.613

Gnomad4 OTH exome AF: 0.644

GnomAD4 genome AF: 0.634 AC: 96251 AN: 151880 Hom.: 30974 Cov.: 30 AF XY: 0.640 AC XY: 47528 AN XY: 74222

Gnomad4 AFR AF: 0.565

Gnomad4 AMR AF: 0.693

Gnomad4 ASJ AF: 0.685

Gnomad4 EAS AF: 0.945

Gnomad4 SAS AF: 0.703

Gnomad4 FIN AF: 0.670

Gnomad4 NFE AF: 0.626

Gnomad4 OTH AF: 0.648

Alfa AF: 0.637 Hom.: 70459

Bravo AF: 0.631

TwinsUK AF: 0.612 AC: 2268

ALSPAC AF: 0.604 AC: 2326

ESP6500AA AF: 0.560 AC: 2468

ESP6500EA AF: 0.630 AC: 5418

ExAC AF: 0.663 AC: 80462

Asia WGS AF: 0.808 AC: 2808 AN: 3478

EpiCase AF: 0.622

EpiControl AF: 0.630

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2019	This variant is associated with the following publications: (PMID: 30389748, 31178129) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.062
DANN	Benign	0.68
DEOGEN2	Benign	0.0018	.;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.33	T;T
MetaRNN	Benign	0.0000011	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.32	.;N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.34	T
REVEL	Benign	0.071
Polyphen		0.0	.;B
MPC		0.18
ClinPred		0.026	T
GERP RS		-11
Varity_R		0.064
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11057353; hg19: chr12-124265687; COSMIC: COSV68997523;