13-100532213-C-T

Variant names:

• chr13-100532213-C-T
• rs967601270
• NM_001195087.2:c.379G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001195087.2(GGACT):​c.379G>A​(p.Glu127Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GGACT NM_001195087.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.79

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28029978).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GGACT	NM_001195087.2	c.379G>A	p.Glu127Lys	missense_variant	Exon 3 of 3	ENST00000683975.1	NP_001182016.1
GGACT	NM_033110.3	c.379G>A	p.Glu127Lys	missense_variant	Exon 2 of 2		NP_149101.1
GGACT	XM_011521129.4	c.379G>A	p.Glu127Lys	missense_variant	Exon 3 of 3		XP_011519431.1
GGACT	XM_047430708.1	c.379G>A	p.Glu127Lys	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	c.379G>A	p.Glu127Lys	missense_variant	Exon 3 of 3		NM_001195087.2	ENSP00000508020.1
GGACT	ENST00000455100.2	c.379G>A	p.Glu127Lys	missense_variant	Exon 2 of 2	1		ENSP00000410449.1
GGACT	ENST00000376250.6	c.379G>A	p.Glu127Lys	missense_variant	Exon 3 of 3	3		ENSP00000365426.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 08, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.379G>A (p.E127K) 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 379, causing the glutamic acid (E) at amino acid position 127 to be replaced by a lysine (K). 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	Benign	0.23
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.026	T;T
Eigen	Benign	-0.0036
Eigen_PC	Benign	-0.0020
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	T;.
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.1	M;M
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Benign	0.13
Sift	Benign	0.050	D;D
Sift4G	Benign	0.15	T;T
Polyphen		0.80	P;P
Vest4		0.18
MutPred		0.41		Gain of methylation at E127 (P = 0.0016);Gain of methylation at E127 (P = 0.0016);
MVP		0.081
ClinPred		0.83	D
GERP RS		4.2
Varity_R		0.51
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: rs967601270; hg19: chr13-101184467;