Genetic Variant DPY19L2:c.804-8_804-5dupTTTT (chr12-63626530-T-TAAAA) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_173812.5(DPY19L2):c.804-8_804-5dupTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0029 ( 39 hom. )

Failed GnomAD Quality Control

Consequence

DPY19L2
NM_173812.5 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.702

Publications

1 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: Likely_benign. The variant received -4 ACMG points.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000236 (30/127298) while in subpopulation EAS AF = 0.00185 (8/4316). AF 95% confidence interval is 0.000922. There are 0 homozygotes in GnomAd4. There are 19 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPY19L2	NM_173812.5 link	c.804-8_804-5dupTTTT		splice_region_variant, intron_variant	Intron 6 of 21	ENST00000324472.9	NP_776173.3

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
DPY19L2	ENST00000324472.9 link	c.804-5_804-4insTTTT	splice_region_variant, intron_variant	Intron 6 of 21	1	NM_173812.5	ENSP00000315988.4
DPY19L2	ENST00000306389.7 link	n.287-5_287-4insTTTT	splice_region_variant, intron_variant	Intron 5 of 13	1		ENSP00000445878.1
ENSG00000249753	ENST00000509615.2 link	n.239-2707_239-2706insTTTT	intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes

AF:

0.000236

AC:

AN:

127312

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00464

Gnomad AMR

AF:

0.000320

Gnomad ASJ

AF:

0.000305

Gnomad EAS

AF:

0.00185

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00379

Gnomad NFE

AF:

0.000193

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00520

AC:

487

AN:

93570

AF XY:

0.00489

show subpopulations

Gnomad AFR exome

AF:

0.00563

Gnomad AMR exome

AF:

0.00693

Gnomad ASJ exome

AF:

0.00355

Gnomad EAS exome

AF:

0.0188

Gnomad FIN exome

AF:

0.00194

Gnomad NFE exome

AF:

0.00373

Gnomad OTH exome

AF:

0.00686

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00290

AC:

3519

AN:

1212928

Hom.:

Cov.:

AF XY:

0.00300

AC XY:

1797

AN XY:

599868

show subpopulations

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

African (AFR)

AF:

0.00149

AC:

AN:

24858

American (AMR)

AF:

0.00493

AC:

110

AN:

22324

Ashkenazi Jewish (ASJ)

AF:

0.00396

AC:

AN:

19696

East Asian (EAS)

AF:

0.00765

AC:

228

AN:

29798

South Asian (SAS)

AF:

0.00606

AC:

377

AN:

62246

European-Finnish (FIN)

AF:

0.00273

AC:

109

AN:

39884

Middle Eastern (MID)

AF:

0.00207

AC:

AN:

4346

European-Non Finnish (NFE)

AF:

0.00251

AC:

2409

AN:

960434

Other (OTH)

AF:

0.00328

AC:

162

AN:

49342

⚠️ 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: 0.294

Heterozygous variant carriers

286

573

859

1146

1432

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

160

240

320

400

<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:

0.000236

AC:

AN:

127298

Hom.:

Cov.:

AF XY:

0.000313

AC XY:

AN XY:

60752

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31610

American (AMR)

AF:

0.000320

AC:

AN:

12492

Ashkenazi Jewish (ASJ)

AF:

0.000305

AC:

AN:

3274

East Asian (EAS)

AF:

0.00185

AC:

AN:

4316

South Asian (SAS)

AF:

0.00

AC:

AN:

4090

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6388

Middle Eastern (MID)

AF:

0.00413

AC:

AN:

242

European-Non Finnish (NFE)

AF:

0.000193

AC:

AN:

62310

Other (OTH)

AF:

0.00

AC:

AN:

1714

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

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:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.70

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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12-63626530-TA-TAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over