12-63580794-T-C

Variant names:

• chr12-63580794-T-C
• rs181185180
• NM_173812.5:c.1768A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_173812.5(DPY19L2):​c.1768A>G​(p.Ile590Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I590F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: DPY19L2 NM_173812.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.659

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08404145).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPY19L2	NM_173812.5	c.1768A>G	p.Ile590Val	missense_variant	Exon 19 of 22	ENST00000324472.9	NP_776173.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DPY19L2	ENST00000324472.9	c.1768A>G	p.Ile590Val	missense_variant	Exon 19 of 22	1	NM_173812.5	ENSP00000315988.4
DPY19L2	ENST00000413230.6	n.514A>G		non_coding_transcript_exon_variant	Exon 3 of 6	2
DPY19L2	ENST00000439061.6	n.*186+1612A>G		intron_variant	Intron 8 of 10	5		ENSP00000437474.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250468 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135354

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461082 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726828

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	7.0
DANN	Benign	0.18
DEOGEN2	Benign	0.0015	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.21	N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.11	N
REVEL	Benign	0.066
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.084
MutPred		0.52		Gain of catalytic residue at L594 (P = 0.0197);
MVP		0.23
MPC		0.15
ClinPred		0.020	T
GERP RS		-0.19
Varity_R		0.025
gMVP		0.48

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

LitVar

Other links and lift over

dbSNP: rs181185180; hg19: chr12-63974574;