14-91170188-C-T

Position:

• chr14-91170188-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PVS1_Moderate BA1

The NM_024952.8(DGLUCY):​c.441+2C>T variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 1,613,068 control chromosomes in the GnomAD database, including 82,216 homozygotes. In-silico tool predicts a benign outcome for this variant. 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 0.26 (5950 hom., cov: 33)
  • Exomes 𝑓: 0.32 (76266 hom.)
• Consequence: DGLUCY NM_024952.8 splice_donor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.539

Genes affected

DGLUCY (HGNC:20498): (D-glutamate cyclase) Predicted to enable D-glutamate cyclase activity. Predicted to be involved in glutamate metabolic process. Predicted to be located in mitochondrial matrix. [provided by Alliance of Genome Resources, Apr 2022]

DGLUCY (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.09886548 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.6, offset of 0 (no position change), new splice context is: cagGTgggt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.324 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DGLUCY	NM_001102368.3	c.443C>T	p.Ala148Val	missense_variant	5/14	ENST00000256324.15	NP_001095838.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DGLUCY	ENST00000256324.15	c.443C>T	p.Ala148Val	missense_variant	5/14	1	NM_001102368.3	ENSP00000256324.9

Frequencies

GnomAD3 genomes AF: 0.263 AC: 40031 AN: 152074 Hom.: 5949 Cov.: 33

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.327

Gnomad AMR AF: 0.258

Gnomad ASJ AF: 0.318

Gnomad EAS AF: 0.0582

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.422

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.328

Gnomad OTH AF: 0.236

GnomAD3 exomes AF: 0.279 AC: 69692 AN: 249580 Hom.: 10894 AF XY: 0.279 AC XY: 37649 AN XY: 135014

Gnomad AFR exome AF: 0.147

Gnomad AMR exome AF: 0.275

Gnomad ASJ exome AF: 0.306

Gnomad EAS exome AF: 0.0576

Gnomad SAS exome AF: 0.199

Gnomad FIN exome AF: 0.418

Gnomad NFE exome AF: 0.329

Gnomad OTH exome AF: 0.280

GnomAD4 exome AF: 0.316 AC: 461082 AN: 1460876 Hom.: 76266 Cov.: 38 AF XY: 0.312 AC XY: 226883 AN XY: 726740

Gnomad4 AFR exome AF: 0.141

Gnomad4 AMR exome AF: 0.271

Gnomad4 ASJ exome AF: 0.307

Gnomad4 EAS exome AF: 0.0561

Gnomad4 SAS exome AF: 0.201

Gnomad4 FIN exome AF: 0.409

Gnomad4 NFE exome AF: 0.339

Gnomad4 OTH exome AF: 0.286

GnomAD4 genome AF: 0.263 AC: 40032 AN: 152192 Hom.: 5950 Cov.: 33 AF XY: 0.265 AC XY: 19706 AN XY: 74398

Gnomad4 AFR AF: 0.148

Gnomad4 AMR AF: 0.257

Gnomad4 ASJ AF: 0.318

Gnomad4 EAS AF: 0.0579

Gnomad4 SAS AF: 0.192

Gnomad4 FIN AF: 0.422

Gnomad4 NFE AF: 0.328

Gnomad4 OTH AF: 0.233

Alfa AF: 0.300 Hom.: 10554

Bravo AF: 0.248

TwinsUK AF: 0.355 AC: 1316

ALSPAC AF: 0.342 AC: 1317

ESP6500AA AF: 0.161 AC: 711

ESP6500EA AF: 0.337 AC: 2897

ExAC AF: 0.275 AC: 33356

Asia WGS AF: 0.148 AC: 516 AN: 3478

EpiCase AF: 0.319

EpiControl AF: 0.322

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.90	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.021
DANN	Benign	0.40
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0072	N
ClinPred		0.0053	T
GERP RS		-5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs4900072; hg19: chr14-91636532;