Genetic Variant GGACT:p.Cys84Tyr (chr13-100532341-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001195087.2(GGACT):c.251G>A(p.Cys84Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000715 in 1,398,220 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

GGACT
NM_001195087.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.86

Variant links:

Genes affected

GGACT (HGNC:25100): (gamma-glutamylamine cyclotransferase) The protein encoded by this gene aids in the proteolytic degradation of crosslinked fibrin by breaking down isodipeptide L-gamma-glutamyl-L-epsilon-lysine, a byproduct of fibrin degradation. The reaction catalyzed by the encoded gamma-glutamylaminecyclotransferase produces 5-oxo-L-proline and a free alkylamine. Two transcript variants encoding the same protein have been found for this gene.[provided by RefSeq, Aug 2010]

GGACT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GGACT	NM_001195087.2 link	c.251G>A	p.Cys84Tyr	missense_variant	Exon 3 of 3	ENST00000683975.1	NP_001182016.1	Q9BVM4
GGACT	NM_033110.3 link	c.251G>A	p.Cys84Tyr	missense_variant	Exon 2 of 2		NP_149101.1	Q9BVM4
GGACT	XM_011521129.4 link	c.251G>A	p.Cys84Tyr	missense_variant	Exon 3 of 3		XP_011519431.1	Q9BVM4
GGACT	XM_047430708.1 link	c.251G>A	p.Cys84Tyr	missense_variant	Exon 3 of 3		XP_047286664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GGACT	ENST00000683975.1 link	c.251G>A	p.Cys84Tyr	missense_variant	Exon 3 of 3		NM_001195087.2	ENSP00000508020.1		Q9BVM4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000666

AC:

AN:

150142

Hom.:

AF XY:

0.0000125

AC XY:

AN XY:

80286

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000929

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.15e-7

AC:

AN:

1398220

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

689660

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.251G>A (p.C84Y) alteration is located in exon 2 (coding exon 1) of the A2LD1 gene. This alteration results from a G to A substitution at nucleotide position 251, causing the cysteine (C) at amino acid position 84 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.15

T;T

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.84

T;.

M_CAP

Benign

0.054

MetaRNN

Uncertain

0.60

D;D

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

L;L

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-5.9

D;D

REVEL

Uncertain

0.34

Sift

Benign

0.059

T;T

Sift4G

Benign

0.91

T;T

Polyphen

1.0

D;D

Vest4

0.55

MutPred

0.55

Gain of catalytic residue at A86 (P = 0.0711);Gain of catalytic residue at A86 (P = 0.0711);

MVP

0.22

ClinPred

0.91

GERP RS

5.2

Varity_R

0.65

gMVP

0.88

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over