Genetic Variant DNAH12:p.Gly3863Arg (chr3-57296381-C-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001366028.2(DNAH12):c.11587G>C(p.Gly3863Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000215 in 1,398,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

DNAH12
NM_001366028.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.64

Publications

0 publications found

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]

DNAH12 Gene-Disease associations (from GenCC):

spermatogenic failure
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
oligoasthenoteratozoospermia
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

DNAH12 links:

ENSG00000286952 (HGNC:):

ENSG00000286952 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.966

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001366028.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH12	NM_001366028.2	MANE Select	c.11587G>C	p.Gly3863Arg	missense	Exon 72 of 74	NP_001352957.1	E9PG32

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNAH12	ENST00000495027.6	TSL:5 MANE Select	c.11587G>C	p.Gly3863Arg	missense	Exon 72 of 74	ENSP00000418137.2	E9PG32
DNAH12	ENST00000351747.6	TSL:5	c.8983G>C	p.Gly2995Arg	missense	Exon 57 of 59	ENSP00000295937.3	Q6ZR08-1
DNAH12	ENST00000466540.2	TSL:5	c.1924G>C	p.Gly642Arg	missense	Exon 13 of 15	ENSP00000420359.2	H7C5N3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000215

AC:

AN:

1398114

Hom.:

Cov.:

AF XY:

0.00000290

AC XY:

AN XY:

689560

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31580

American (AMR)

AF:

0.00

AC:

AN:

35686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25122

East Asian (EAS)

AF:

0.0000840

AC:

AN:

35720

South Asian (SAS)

AF:

0.00

AC:

AN:

79026

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49240

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5674

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078124

Other (OTH)

AF:

0.00

AC:

AN:

57942

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.20

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

0.86

MutationAssessor

Pathogenic

4.5

PhyloP100

7.6

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-6.7

REVEL

Pathogenic

0.66

Sift

Pathogenic

0.0

Polyphen

1.0

Vest4

0.94

MutPred

0.85

Gain of glycosylation at Y2992 (P = 0.0031)

MVP

0.71

ClinPred

1.0

GERP RS

4.9

Varity_R

0.90

Mutation Taster

=37/63

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over