chr14-91170188-C-T

Variant names:

• chr14-91170188-C-T
• rs4900072
• NM_001102368.3:c.443C>T

Variant summary

Our verdict is Likely benign. The variant received -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
• Publications: 28 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.09940573 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024952.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DGLUCY	NM_001102368.3	MANE Select	c.443C>T	p.Ala148Val	missense	Exon 5 of 14	NP_001095838.1
	DGLUCY	NM_001286470.2		c.443C>T	p.Ala148Val	missense	Exon 8 of 17	NP_001273399.1
	DGLUCY	NM_001358310.2		c.443C>T	p.Ala148Val	missense	Exon 5 of 14	NP_001345239.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DGLUCY	ENST00000256324.15	TSL:1 MANE Select	c.443C>T	p.Ala148Val	missense	Exon 5 of 14	ENSP00000256324.9
	DGLUCY	ENST00000521077.6	TSL:1	c.443C>T	p.Ala148Val	missense	Exon 7 of 15	ENSP00000430137.1
	DGLUCY	ENST00000517518.5	TSL:1	c.443C>T	p.Ala148Val	missense	Exon 6 of 11	ENSP00000428652.1

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

GnomAD2 exomes AF: 0.279 AC: 69692 AN: 249580 AF XY: 0.279

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 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

African (AFR) AF: 0.141 AC: 4702 AN: 33460

American (AMR) AF: 0.271 AC: 12104 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 8020 AN: 26120

East Asian (EAS) AF: 0.0561 AC: 2225 AN: 39694

South Asian (SAS) AF: 0.201 AC: 17295 AN: 86228

European-Finnish (FIN) AF: 0.409 AC: 21685 AN: 53084

Middle Eastern (MID) AF: 0.259 AC: 1450 AN: 5608

European-Non Finnish (NFE) AF: 0.339 AC: 376338 AN: 1111664

Other (OTH) AF: 0.286 AC: 17263 AN: 60344

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

African (AFR) AF: 0.148 AC: 6159 AN: 41532

American (AMR) AF: 0.257 AC: 3937 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.318 AC: 1105 AN: 3472

East Asian (EAS) AF: 0.0579 AC: 300 AN: 5178

South Asian (SAS) AF: 0.192 AC: 929 AN: 4826

European-Finnish (FIN) AF: 0.422 AC: 4463 AN: 10578

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.328 AC: 22269 AN: 67988

Other (OTH) AF: 0.233 AC: 491 AN: 2108

Alfa AF: 0.297 Hom.: 13707

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
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
PhyloP100		-0.54
ClinPred		0.0053	T
GERP RS		-5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=92/8	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4900072; hg19: chr14-91636532;