12-123909293-C-T

Variant names:

• chr12-123909293-C-T
• rs191384577
• NM_001372106.1:c.9848C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001372106.1(DNAH10):​c.9848C>T​(p.Thr3283Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00234 in 1,613,458 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T3283R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (6 hom.)
• Consequence: DNAH10 NM_001372106.1 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.13
• Publications: 6 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012706608).
• BP6: Variant 12-123909293-C-T is Benign according to our data. Variant chr12-123909293-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 402627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

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.9848C>T	p.Thr3283Met	missense	Exon 58 of 79	NP_001359035.1
	DNAH10	NM_207437.3		c.9494C>T	p.Thr3165Met	missense	Exon 57 of 78	NP_997320.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH10	ENST00000673944.1	MANE Select	c.9848C>T	p.Thr3283Met	missense	Exon 58 of 79	ENSP00000501095.1
	DNAH10	ENST00000409039.8	TSL:5	c.9677C>T	p.Thr3226Met	missense	Exon 57 of 78	ENSP00000386770.4
	DNAH10	ENST00000638045.1	TSL:5	c.9494C>T	p.Thr3165Met	missense	Exon 57 of 78	ENSP00000489675.1

Frequencies

GnomAD3 genomes AF: 0.00183 AC: 278 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00517

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00235

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00158 AC: 390 AN: 247452 AF XY: 0.00162

Gnomad AFR exome AF: 0.000262

Gnomad AMR exome AF: 0.00180

Gnomad ASJ exome AF: 0.00110

Gnomad EAS exome AF: 0.0000558

Gnomad FIN exome AF: 0.000697

Gnomad NFE exome AF: 0.00226

Gnomad OTH exome AF: 0.00183

GnomAD4 exome AF: 0.00239 AC: 3495 AN: 1461116 Hom.: 6 Cov.: 32 AF XY: 0.00227 AC XY: 1648 AN XY: 726720

African (AFR) AF: 0.000448 AC: 15 AN: 33472

American (AMR) AF: 0.00222 AC: 99 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00103 AC: 27 AN: 26120

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.00103 AC: 89 AN: 86064

European-Finnish (FIN) AF: 0.000620 AC: 33 AN: 53238

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5766

European-Non Finnish (NFE) AF: 0.00276 AC: 3073 AN: 1111726

Other (OTH) AF: 0.00245 AC: 148 AN: 60364

GnomAD4 genome AF: 0.00182 AC: 278 AN: 152342 Hom.: 0 Cov.: 32 AF XY: 0.00168 AC XY: 125 AN XY: 74502

African (AFR) AF: 0.000433 AC: 18 AN: 41578

American (AMR) AF: 0.00516 AC: 79 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4832

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00235 AC: 160 AN: 68032

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00211 Hom.: 1

Bravo AF: 0.00275

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000257 AC: 1

ESP6500EA AF: 0.00229 AC: 19

ExAC AF: 0.00133 AC: 161

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00284

EpiControl AF: 0.00238

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.74	N
PhyloP100		3.1
PrimateAI	Uncertain	0.54	T
REVEL	Benign	0.20
Sift4G	Uncertain	0.0050	D
Polyphen		0.77	P
MVP		0.63
MPC		0.17
ClinPred		0.021	T
GERP RS		5.6
Varity_R		0.070
gMVP		0.37
Mutation Taster		=94/6	polymorphism

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: rs191384577; hg19: chr12-124393840;