NM_000359.3:c.1559A>G

Variant names:

• chr14-24255450-T-C
• rs142404759
• NM_000359.3:c.1559A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_000359.3(TGM1):​c.1559A>G​(p.Glu520Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00798 in 1,614,004 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E520K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0053 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0083 (64 hom.)
• Consequence: TGM1 NM_000359.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 1.59
• Publications: 15 publications found

Genes affected

TGM1 (HGNC:11777): (transglutaminase 1) The protein encoded by this gene is a membrane protein that catalyzes the addition of an alkyl group from an akylamine to a glutamine residue of a protein, forming an alkylglutamine in the protein. This protein alkylation leads to crosslinking of proteins and catenation of polyamines to proteins. This gene contains either one or two copies of a 22 nt repeat unit in its 3' UTR. Mutations in this gene have been associated with autosomal recessive lamellar ichthyosis (LI) and nonbullous congenital ichthyosiform erythroderma (NCIE). [provided by RefSeq, Jul 2008]

TGM1 Gene-Disease associations (from GenCC):

• autosomal recessive congenital ichthyosis 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, Myriad Women’s Health, G2P
• acral self-healing collodion baby

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• bathing suit ichthyosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital non-bullous ichthyosiform erythroderma

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• lamellar ichthyosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• self-healing collodion baby

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 81 curated pathogenic missense variants (we use a threshold of 10). The gene has 20 curated benign missense variants. Gene score misZ: -0.060191 (below the threshold of 3.09). Trascript score misZ: 1.7514 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal recessive congenital ichthyosis 1, acral self-healing collodion baby, bathing suit ichthyosis, congenital non-bullous ichthyosiform erythroderma, lamellar ichthyosis, self-healing collodion baby.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0060895383).
• BP6: Variant 14-24255450-T-C is Benign according to our data. Variant chr14-24255450-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 235714.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00534 (813/152118) while in subpopulation NFE AF = 0.00918 (624/67996). AF 95% confidence interval is 0.00858. There are 5 homozygotes in GnomAd4. There are 389 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000359.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGM1	NM_000359.3	MANE Select	c.1559A>G	p.Glu520Gly	missense	Exon 11 of 15	NP_000350.1	P22735-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGM1	ENST00000206765.11	TSL:1 MANE Select	c.1559A>G	p.Glu520Gly	missense	Exon 11 of 15	ENSP00000206765.6	P22735-1
	TGM1	ENST00000879556.1		c.1559A>G	p.Glu520Gly	missense	Exon 10 of 14	ENSP00000549615.1
	TGM1	ENST00000544573.5	TSL:2	c.233A>G	p.Glu78Gly	missense	Exon 5 of 9	ENSP00000439446.1	P22735-2

Frequencies

GnomAD3 genomes AF: 0.00535 AC: 813 AN: 152000 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00160

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00623

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00918

Gnomad OTH AF: 0.00624

GnomAD2 exomes AF: 0.00571 AC: 1435 AN: 251384 AF XY: 0.00564

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00202

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00661

Gnomad NFE exome AF: 0.00963

Gnomad OTH exome AF: 0.00603

GnomAD4 exome AF: 0.00826 AC: 12070 AN: 1461886 Hom.: 64 Cov.: 34 AF XY: 0.00809 AC XY: 5886 AN XY: 727244

African (AFR) AF: 0.00116 AC: 39 AN: 33480

American (AMR) AF: 0.00201 AC: 90 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00107 AC: 28 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00192 AC: 166 AN: 86258

European-Finnish (FIN) AF: 0.00584 AC: 312 AN: 53420

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.00997 AC: 11090 AN: 1112010

Other (OTH) AF: 0.00555 AC: 335 AN: 60392

GnomAD4 genome AF: 0.00534 AC: 813 AN: 152118 Hom.: 5 Cov.: 32 AF XY: 0.00523 AC XY: 389 AN XY: 74360

African (AFR) AF: 0.00159 AC: 66 AN: 41484

American (AMR) AF: 0.00249 AC: 38 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4822

European-Finnish (FIN) AF: 0.00623 AC: 66 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00918 AC: 624 AN: 67996

Other (OTH) AF: 0.00618 AC: 13 AN: 2104

Alfa AF: 0.00818 Hom.: 14

Bravo AF: 0.00526

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.00779 AC: 67

ExAC AF: 0.00567 AC: 688

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00802

EpiControl AF: 0.00984

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	1	2	Autosomal recessive congenital ichthyosis 1 (3)
-	-	1	not specified (1)
-	-	1	TGM1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Benign	0.14
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.63	D
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.6
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.52
Sift	Benign	0.085	T
Sift4G	Benign	0.086	T
Polyphen		0.96	P
Vest4		0.21
MVP		0.93
MPC		0.98
ClinPred		0.036	T
GERP RS		5.4
PromoterAI		-0.026	Neutral
Varity_R		0.34
gMVP		0.58
Mutation Taster		=77/23	polymorphism

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: rs142404759; hg19: chr14-24724656;