12-63626530-TA-TAA

Variant names:

• chr12-63626530-T-TA
• rs371578418
• NM_173812.5:c.804-5dupT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_173812.5(DPY19L2):​c.804-5dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.17 (1924 hom., cov: 0)
  • Exomes 𝑓: 0.15 (1506 hom.)
  • Failed GnomAD Quality Control
• Consequence: DPY19L2 NM_173812.5 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.702
• Publications: 1 publications found

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

ENSG00000249753 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.18 is higher than 0.05.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.167 AC: 21082 AN: 126596 Hom.: 1923 Cov.: 0

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.185

Gnomad AMR AF: 0.146

Gnomad ASJ AF: 0.182

Gnomad EAS AF: 0.0141

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.163

Gnomad NFE AF: 0.183

Gnomad OTH AF: 0.165

GnomAD2 exomes AF: 0.148 AC: 13813 AN: 93570 AF XY: 0.147

Gnomad AFR exome AF: 0.168

Gnomad AMR exome AF: 0.161

Gnomad ASJ exome AF: 0.198

Gnomad EAS exome AF: 0.139

Gnomad FIN exome AF: 0.145

Gnomad NFE exome AF: 0.135

Gnomad OTH exome AF: 0.158

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.155 AC: 171860 AN: 1109180 Hom.: 1506 Cov.: 33 AF XY: 0.153 AC XY: 84044 AN XY: 548300

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

African (AFR) AF: 0.155 AC: 3681 AN: 23712

American (AMR) AF: 0.135 AC: 2855 AN: 21190

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 3079 AN: 18328

East Asian (EAS) AF: 0.111 AC: 3141 AN: 28338

South Asian (SAS) AF: 0.133 AC: 7712 AN: 58138

European-Finnish (FIN) AF: 0.139 AC: 5129 AN: 36952

Middle Eastern (MID) AF: 0.159 AC: 644 AN: 4058

European-Non Finnish (NFE) AF: 0.159 AC: 138567 AN: 872964

Other (OTH) AF: 0.155 AC: 7052 AN: 45500

⚠️ 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.

GnomAD4 genome AF: 0.166 AC: 21075 AN: 126580 Hom.: 1924 Cov.: 0 AF XY: 0.162 AC XY: 9806 AN XY: 60386

African (AFR) AF: 0.178 AC: 5595 AN: 31480

American (AMR) AF: 0.145 AC: 1803 AN: 12400

Ashkenazi Jewish (ASJ) AF: 0.182 AC: 592 AN: 3254

East Asian (EAS) AF: 0.0141 AC: 61 AN: 4314

South Asian (SAS) AF: 0.105 AC: 429 AN: 4070

European-Finnish (FIN) AF: 0.124 AC: 786 AN: 6334

Middle Eastern (MID) AF: 0.148 AC: 35 AN: 236

European-Non Finnish (NFE) AF: 0.183 AC: 11338 AN: 61946

Other (OTH) AF: 0.164 AC: 277 AN: 1688

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.70
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs371578418; hg19: chr12-64020310; COSMIC: COSV60543524;