12-63626530-TA-TAAA

Variant names:

• chr12-63626530-T-TAA
• rs371578418
• NM_173812.5:c.804-6_804-5dupTT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_173812.5(DPY19L2):​c.804-6_804-5dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.22 (3465 hom., cov: 0)
  • Exomes 𝑓: 0.13 (1378 hom.)
  • Failed GnomAD Quality Control
• Consequence: DPY19L2 NM_173812.5 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant 12-63626530-T-TAA is Benign according to our data. Variant chr12-63626530-T-TAA is described in ClinVar as Benign. ClinVar VariationId is 402795.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.309 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.224 AC: 28259 AN: 125954 Hom.: 3462 Cov.: 0

Gnomad AFR AF: 0.187

Gnomad AMI AF: 0.325

Gnomad AMR AF: 0.270

Gnomad ASJ AF: 0.305

Gnomad EAS AF: 0.314

Gnomad SAS AF: 0.324

Gnomad FIN AF: 0.164

Gnomad MID AF: 0.235

Gnomad NFE AF: 0.222

Gnomad OTH AF: 0.225

GnomAD2 exomes AF: 0.0800 AC: 7483 AN: 93570 AF XY: 0.0790

Gnomad AFR exome AF: 0.0947

Gnomad AMR exome AF: 0.117

Gnomad ASJ exome AF: 0.101

Gnomad EAS exome AF: 0.130

Gnomad FIN exome AF: 0.0651

Gnomad NFE exome AF: 0.0610

Gnomad OTH exome AF: 0.0849

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.127 AC: 140485 AN: 1110554 Hom.: 1378 Cov.: 33 AF XY: 0.126 AC XY: 69045 AN XY: 549214

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

African (AFR) AF: 0.115 AC: 2705 AN: 23484

American (AMR) AF: 0.114 AC: 2415 AN: 21276

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 2660 AN: 18336

East Asian (EAS) AF: 0.168 AC: 4639 AN: 27532

South Asian (SAS) AF: 0.138 AC: 7972 AN: 57764

European-Finnish (FIN) AF: 0.0917 AC: 3464 AN: 37782

Middle Eastern (MID) AF: 0.120 AC: 487 AN: 4074

European-Non Finnish (NFE) AF: 0.126 AC: 110324 AN: 875068

Other (OTH) AF: 0.129 AC: 5819 AN: 45238

⚠️ 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: 0.224 AC: 28261 AN: 125942 Hom.: 3465 Cov.: 0 AF XY: 0.226 AC XY: 13562 AN XY: 60076

African (AFR) AF: 0.187 AC: 5860 AN: 31352

American (AMR) AF: 0.271 AC: 3337 AN: 12336

Ashkenazi Jewish (ASJ) AF: 0.305 AC: 985 AN: 3230

East Asian (EAS) AF: 0.315 AC: 1345 AN: 4270

South Asian (SAS) AF: 0.323 AC: 1291 AN: 3992

European-Finnish (FIN) AF: 0.164 AC: 1026 AN: 6268

Middle Eastern (MID) AF: 0.252 AC: 61 AN: 242

European-Non Finnish (NFE) AF: 0.222 AC: 13698 AN: 61714

Other (OTH) AF: 0.226 AC: 383 AN: 1692

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.70
Mutation Taster		=99/1	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs371578418; hg19: chr12-64020310;