chr12-63624124-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP5BS1_Supporting

The NM_173812.5(DPY19L2):c.869G>A(p.Arg290His) variant causes a missense change. The variant allele was found at a frequency of 0.000452 in 1,610,850 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R290P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00048 ( 1 hom. )

Consequence

DPY19L2
NM_173812.5 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 5.68

Publications

11 publications found

Variant links:

Genes affected

DPY19L2 (HGNC:19414): (dpy-19 like 2) The protein encoded by this gene belongs to the dpy-19 family. It is highly expressed in testis, and is required for sperm head elongation and acrosome formation during spermatogenesis. Mutations in this gene are associated with an infertility disorder, spermatogenic failure type 9 (SPGF9). [provided by RefSeq, Dec 2011]

DPY19L2 Gene-Disease associations (from GenCC):

spermatogenic failure 9
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
male infertility due to globozoospermia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

DPY19L2 links:

ENSG00000249753 (HGNC:):

ENSG00000249753 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PP5

Variant 12-63624124-C-T is Pathogenic according to our data. Variant chr12-63624124-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 101504.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000476 (694/1458640) while in subpopulation NFE AF = 0.000599 (665/1110908). AF 95% confidence interval is 0.000561. There are 1 homozygotes in GnomAdExome4. There are 310 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPY19L2	NM_173812.5 link	c.869G>A	p.Arg290His	missense_variant	Exon 8 of 22	ENST00000324472.9	NP_776173.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
DPY19L2	ENST00000324472.9 link	c.869G>A	p.Arg290His	missense_variant	Exon 8 of 22	1	NM_173812.5	ENSP00000315988.4
DPY19L2	ENST00000306389.7 link	n.*344+2345G>A		intron_variant	Intron 6 of 13	1		ENSP00000445878.1
ENSG00000249753	ENST00000509615.2 link	n.239-300G>A		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes

AF:

0.000224

AC:

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000368

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000172

AC:

AN:

250618

AF XY:

0.000177

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000309

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000476

AC:

694

AN:

1458640

Hom.:

Cov.:

AF XY:

0.000427

AC XY:

310

AN XY:

725648

show subpopulations

African (AFR)

AF:

0.0000599

AC:

AN:

33390

American (AMR)

AF:

0.0000671

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86108

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53378

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4198

European-Non Finnish (NFE)

AF:

0.000599

AC:

665

AN:

1110908

Other (OTH)

AF:

0.000349

AC:

AN:

60172

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

107

143

179

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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:

0.000223

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.0000963

AC:

AN:

41532

American (AMR)

AF:

0.000262

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0000944

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000368

AC:

AN:

68006

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

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:

0.000332

Hom.:

Bravo

AF:

0.000238

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000198

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000771

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Spermatogenic failure 9

Pathogenic:1

Aug 15, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.052

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.19

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.85

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.73

MetaSVM

Benign

-0.82

PhyloP100

5.7

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-4.3

REVEL

Uncertain

0.61

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.97

MVP

0.67

MPC

2.4

ClinPred

0.25

GERP RS

2.8

Varity_R

0.59

gMVP

0.87

Mutation Taster

=43/57

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over