Genetic Variant DNAH12:p.Arg3902Leu (chr3-57293959-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001366028.2(DNAH12):c.11705G>T(p.Arg3902Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000571 in 1,225,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3902Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000057 ( 0 hom. )

Consequence

DNAH12
NM_001366028.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.196

Publications

1 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.097075194).

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.11705G>T	p.Arg3902Leu	missense	Exon 74 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.11705G>T	p.Arg3902Leu	missense	Exon 74 of 74	ENSP00000418137.2	E9PG32
DNAH12	ENST00000351747.6	TSL:5	c.9101G>T	p.Arg3034Leu	missense	Exon 59 of 59	ENSP00000295937.3	Q6ZR08-1
DNAH12	ENST00000466540.2	TSL:5	c.2042G>T	p.Arg681Leu	missense	Exon 15 of 15	ENSP00000420359.2	H7C5N3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000571

AC:

AN:

1225750

Hom.:

Cov.:

AF XY:

0.00000505

AC XY:

AN XY:

593832

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

25426

American (AMR)

AF:

0.00

AC:

AN:

15784

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19484

East Asian (EAS)

AF:

0.00

AC:

AN:

30038

South Asian (SAS)

AF:

0.0000583

AC:

AN:

51462

European-Finnish (FIN)

AF:

0.0000232

AC:

AN:

43196

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4982

European-Non Finnish (NFE)

AF:

0.00000304

AC:

AN:

986146

Other (OTH)

AF:

0.00

AC:

AN:

49232

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.232

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.017

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.28

M_CAP

Benign

0.061

MetaRNN

Benign

0.097

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.3

PhyloP100

0.20

PrimateAI

Benign

0.24

PROVEAN

Benign

-2.0

REVEL

Benign

0.079

Sift

Uncertain

0.0090

Polyphen

0.30

Vest4

0.10

MutPred

0.45

Gain of glycosylation at T3030 (P = 0.0483)

MVP

0.24

ClinPred

0.71

GERP RS

3.2

Varity_R

0.082

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over