NM_001372106.1:c.1621A>G

Variant names:

• chr12-123789927-A-G
• rs10846559
• NM_001372106.1:c.1621A>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.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. 17/23 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I541F) has been classified as Uncertain significance.

• 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
• Publications: 31 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: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
• primary ciliary dyskinesia

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

LOC105370044 (HGNC:):

ACMG classification

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

• 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 VariationId is 402614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.973 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH10	NM_001372106.1	MANE Select	c.1621A>G	p.Ile541Val	missense splice_region	Exon 11 of 79	NP_001359035.1	A0A669KB38
	DNAH10	NM_207437.3		c.1438A>G	p.Ile480Val	missense splice_region	Exon 11 of 78	NP_997320.2	B0I1S1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH10	ENST00000673944.1	MANE Select	c.1621A>G	p.Ile541Val	missense splice_region	Exon 11 of 79	ENSP00000501095.1	A0A669KB38
	DNAH10	ENST00000447853.2	TSL:1	n.953A>G		splice_region non_coding_transcript_exon	Exon 6 of 15
	DNAH10	ENST00000409039.8	TSL:5	c.1621A>G	p.Ile541Val	missense splice_region	Exon 11 of 78	ENSP00000386770.4	A0A1C7CYW8

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

GnomAD2 exomes AF: 0.728 AC: 181347 AN: 249100 AF XY: 0.723

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 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

African (AFR) AF: 0.851 AC: 28431 AN: 33394

American (AMR) AF: 0.767 AC: 33993 AN: 44332

Ashkenazi Jewish (ASJ) AF: 0.732 AC: 19078 AN: 26052

East Asian (EAS) AF: 0.999 AC: 39591 AN: 39622

South Asian (SAS) AF: 0.724 AC: 62053 AN: 85676

European-Finnish (FIN) AF: 0.685 AC: 36576 AN: 53390

Middle Eastern (MID) AF: 0.669 AC: 3839 AN: 5736

European-Non Finnish (NFE) AF: 0.652 AC: 723337 AN: 1109034

Other (OTH) AF: 0.702 AC: 42264 AN: 60218

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

African (AFR) AF: 0.849 AC: 35254 AN: 41506

American (AMR) AF: 0.772 AC: 11806 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.729 AC: 2528 AN: 3470

East Asian (EAS) AF: 0.996 AC: 5162 AN: 5182

South Asian (SAS) AF: 0.753 AC: 3614 AN: 4800

European-Finnish (FIN) AF: 0.684 AC: 7224 AN: 10560

Middle Eastern (MID) AF: 0.697 AC: 205 AN: 294

European-Non Finnish (NFE) AF: 0.664 AC: 45099 AN: 67970

Other (OTH) AF: 0.751 AC: 1587 AN: 2112

Alfa AF: 0.698 Hom.: 79455

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

ClinVar submissions

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	0.063
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	17
DANN	Benign	0.32
DEOGEN2	Benign	0.0045	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.16	T
MetaRNN	Benign	7.7e-7	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.9	N
PhyloP100		3.4
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
Mutation Taster		=94/6	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10846559; hg19: chr12-124274474; COSMIC: COSV107518018;