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GeneBe

3-57293831-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001366028.2(DNAH12):c.11833C>T(p.Arg3945Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000916 in 1,549,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3945Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000087 ( 0 hom. )

Consequence

DNAH12
NM_001366028.2 missense

Scores

1
2
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.57
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.10026142).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DNAH12NM_001366028.2 linkuse as main transcriptc.11833C>T p.Arg3945Trp missense_variant 74/74 ENST00000495027.6
LOC124909384XR_007095923.1 linkuse as main transcriptn.602+439G>A intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DNAH12ENST00000495027.6 linkuse as main transcriptc.11833C>T p.Arg3945Trp missense_variant 74/745 NM_001366028.2 P1
ENST00000656348.1 linkuse as main transcriptn.310+439G>A intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
AF:
0.000132
AC:
20
AN:
151334
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.000865
Gnomad EAS
AF:
0.000967
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000177
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000766
AC:
12
AN:
156742
Hom.:
0
AF XY:
0.000121
AC XY:
10
AN XY:
82884
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000406
Gnomad ASJ exome
AF:
0.000942
Gnomad EAS exome
AF:
0.0000919
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000329
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000872
AC:
122
AN:
1398484
Hom.:
0
Cov.:
34
AF XY:
0.000101
AC XY:
70
AN XY:
689748
show subpopulations
Gnomad4 AFR exome
AF:
0.0000317
Gnomad4 AMR exome
AF:
0.0000561
Gnomad4 ASJ exome
AF:
0.000517
Gnomad4 EAS exome
AF:
0.0000280
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000406
Gnomad4 NFE exome
AF:
0.0000900
Gnomad4 OTH exome
AF:
0.000104
GnomAD4 genome
AF:
0.000132
AC:
20
AN:
151458
Hom.:
0
Cov.:
31
AF XY:
0.000122
AC XY:
9
AN XY:
73948
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.000865
Gnomad4 EAS
AF:
0.000969
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000177
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000148
Hom.:
0
Bravo
AF:
0.000121
ExAC
AF:
0.000281
AC:
7
Asia WGS
AF:
0.00231
AC:
8
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 12, 2023The c.9229C>T (p.R3077W) alteration is located in exon 59 (coding exon 58) of the DNAH12 gene. This alteration results from a C to T substitution at nucleotide position 9229, causing the arginine (R) at amino acid position 3077 to be replaced by a tryptophan (W). 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
0.13
BayesDel_addAF
Benign
-0.24
T
BayesDel_noAF
Benign
-0.38
Cadd
Benign
23
Dann
Benign
0.97
DEOGEN2
Benign
0.060
T;T
Eigen
Benign
-0.24
Eigen_PC
Benign
-0.24
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.97
D;D
M_CAP
Uncertain
0.21
D
MetaRNN
Benign
0.10
T;T
MetaSVM
Benign
-0.91
T
MutationTaster
Benign
0.99
N;N
PrimateAI
Benign
0.33
T
Polyphen
0.84
.;P
Vest4
0.17
MVP
0.60
ClinPred
0.29
T
GERP RS
3.9
Varity_R
0.29

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs551271680; hg19: chr3-57327859; API