3-57309182-C-A

Variant names:

• chr3-57309182-C-A
• rs2061535604
• NM_001366028.2:c.11158G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001366028.2(DNAH12):​c.11158G>T​(p.Val3720Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000143 in 1,396,772 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DNAH12 NM_001366028.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.12

Genes affected

DNAH12 (HGNC:2943): (dynein axonemal heavy chain 12) Predicted to enable several functions, including ATP binding activity; dynein intermediate chain binding activity; and dynein light intermediate chain binding activity. Predicted to be involved in microtubule-based movement. Predicted to be located in cilium; cytoplasm; and microtubule. Predicted to be part of dynein complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH12	NM_001366028.2	c.11158G>T	p.Val3720Leu	missense_variant	Exon 69 of 74	ENST00000495027.6	NP_001352957.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH12	ENST00000495027.6	c.11158G>T	p.Val3720Leu	missense_variant	Exon 69 of 74	5	NM_001366028.2	ENSP00000418137.2
DNAH12	ENST00000351747.6	c.8554G>T	p.Val2852Leu	missense_variant	Exon 54 of 59	5		ENSP00000295937.3
DNAH12	ENST00000466540.2	c.1495G>T	p.Val499Leu	missense_variant	Exon 10 of 15	5		ENSP00000420359.2
DNAH12	ENST00000494758.5	n.64G>T		non_coding_transcript_exon_variant	Exon 1 of 5	2		ENSP00000420717.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1396772 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 688848

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: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.8554G>T (p.V2852L) alteration is located in exon 54 (coding exon 53) of the DNAH12 gene. This alteration results from a G to T substitution at nucleotide position 8554, causing the valine (V) at amino acid position 2852 to be replaced by a leucine (L). 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	0.95
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Uncertain	0.092	D
MetaRNN	Uncertain	0.66	D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Pathogenic	3.8	.;H
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.5	.;D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	.;D
Polyphen		1.0	.;D
Vest4		0.57
MutPred		0.72		.;Gain of glycosylation at S2848 (P = 0.0789);
MVP		0.66
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.91

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: rs2061535604; hg19: chr3-57343210;