12-123772880-G-C

Position:

• chr12-123772880-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001372106.1(DNAH10):​c.443G>C​(p.Cys148Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: DNAH10 NM_001372106.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0900

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.17174882).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH10	NM_001372106.1	c.443G>C	p.Cys148Ser	missense_variant	4/79	ENST00000673944.1	NP_001359035.1
LOC105370044	XR_945481.4	n.496-7632C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH10	ENST00000673944.1	c.443G>C	p.Cys148Ser	missense_variant	4/79		NM_001372106.1	ENSP00000501095	P1
DNAH10	ENST00000409039.8	c.443G>C	p.Cys148Ser	missense_variant	4/78	5		ENSP00000386770
DNAH10	ENST00000638045.1	c.260G>C	p.Cys87Ser	missense_variant	4/78	5		ENSP00000489675
DNAH10	ENST00000614082.1	c.-287G>C		5_prime_UTR_variant	4/20	5		ENSP00000479072

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460590 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726572

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 13, 2023

The c.260G>C (p.C87S) alteration is located in exon 4 (coding exon 4) of the DNAH10 gene. This alteration results from a G to C substitution at nucleotide position 260, causing the cysteine (C) at amino acid position 87 to be replaced by a serine (S). 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	Benign	0.16
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	4.8
DANN	Benign	0.40
DEOGEN2	Benign	0.0033	.;T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.50	T;T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.8	.;L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.36	T
REVEL	Benign	0.12
Polyphen		0.0	.;B
MutPred		0.65		.;Loss of catalytic residue at M85 (P = 2e-04);
MVP		0.088
MPC		0.18
ClinPred		0.041	T
GERP RS		1.6
Varity_R		0.060
gMVP		0.55

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: rs1957306787; hg19: chr12-124257427;