chr12-123928453-C-T

Variant names:

• chr12-123928453-C-T
• rs1955042690
• NM_001372106.1:c.12172C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001372106.1(DNAH10):​c.12172C>T​(p.Leu4058Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNAH10 NM_001372106.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.92

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH10	NM_001372106.1	c.12172C>T	p.Leu4058Phe	missense_variant	Exon 70 of 79	ENST00000673944.1	NP_001359035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH10	ENST00000673944.1	c.12172C>T	p.Leu4058Phe	missense_variant	Exon 70 of 79		NM_001372106.1	ENSP00000501095.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.11818C>T (p.L3940F) alteration is located in exon 69 (coding exon 69) of the DNAH10 gene. This alteration results from a C to T substitution at nucleotide position 11818, causing the leucine (L) at amino acid position 3940 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	.;T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.052	D
MutationAssessor	Pathogenic	4.6	.;H
PrimateAI	Uncertain	0.69	T
REVEL	Uncertain	0.44
Polyphen		1.0	.;D
MutPred		0.91		.;Loss of ubiquitination at K3943 (P = 0.1191);
MVP		0.40
MPC		0.67
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.95
gMVP		0.70

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: rs1955042690; hg19: chr12-124413000;