Genetic Variant DNAH12:p.Arg3945Gln (chr3-57293830-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_ModerateBP6_Moderate

The NM_001366028.2(DNAH12):c.11834G>A(p.Arg3945Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000031 in 1,549,182 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. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3945W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

DNAH12
NM_001366028.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 5.01

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07013804).

BP6

Variant 3-57293830-C-T is Benign according to our data. Variant chr3-57293830-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2600282.Status of the report is criteria_provided_single_submitter, 1 stars.

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.11834G>A	p.Arg3945Gln	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.11834G>A	p.Arg3945Gln	missense	Exon 74 of 74	ENSP00000418137.2	E9PG32
DNAH12	ENST00000351747.6	TSL:5	c.9230G>A	p.Arg3077Gln	missense	Exon 59 of 59	ENSP00000295937.3	Q6ZR08-1
DNAH12	ENST00000466540.2	TSL:5	c.2171G>A	p.Arg724Gln	missense	Exon 15 of 15	ENSP00000420359.2	H7C5N3

Frequencies

GnomAD3 genomes

AF:

0.0000331

AC:

AN:

150890

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000980

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000319

AC:

AN:

156604

AF XY:

0.0000362

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000238

Gnomad NFE exome

AF:

0.0000165

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000308

AC:

AN:

1398182

Hom.:

Cov.:

AF XY:

0.0000334

AC XY:

AN XY:

689626

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31482

American (AMR)

AF:

0.0000280

AC:

AN:

35660

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25132

East Asian (EAS)

AF:

0.000476

AC:

AN:

35688

South Asian (SAS)

AF:

0.00

AC:

AN:

79090

European-Finnish (FIN)

AF:

0.000264

AC:

AN:

49288

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5688

European-Non Finnish (NFE)

AF:

0.0000111

AC:

AN:

1078196

Other (OTH)

AF:

0.00

AC:

AN:

57958

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

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

AF:

0.0000331

AC:

AN:

151000

Hom.:

Cov.:

AF XY:

0.0000271

AC XY:

AN XY:

73690

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41106

American (AMR)

AF:

0.00

AC:

AN:

15176

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.000388

AC:

AN:

5158

South Asian (SAS)

AF:

0.00

AC:

AN:

4760

European-Finnish (FIN)

AF:

0.0000980

AC:

AN:

10206

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0000295

AC:

AN:

67838

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000534

Hom.:

Bravo

AF:

0.0000264

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.0033

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.75

M_CAP

Benign

0.033

MetaRNN

Benign

0.070

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.2

PhyloP100

5.0

PrimateAI

Benign

0.32

PROVEAN

Benign

1.3

REVEL

Benign

0.085

Sift

Benign

0.31

Polyphen

0.29

Vest4

0.086

MVP

0.43

ClinPred

0.086

GERP RS

4.5

Varity_R

0.067

Mutation Taster

=83/17

polymorphism

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over