20-2340459-G-C

Variant names:

• chr20-2340459-G-C
• rs214830
• NM_003245.4:c.1960G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003245.4(TGM3):​c.1960G>C​(p.Gly654Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.665 in 1,613,766 control chromosomes in the GnomAD database, including 361,557 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G654E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.72 (40619 hom., cov: 30)
  • Exomes 𝑓: 0.66 (320938 hom.)
• Consequence: TGM3 NM_003245.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.635
• Publications: 29 publications found

Genes affected

TGM3 (HGNC:11779): (transglutaminase 3) Transglutaminases are enzymes that catalyze the crosslinking of proteins by epsilon-gamma glutamyl lysine isopeptide bonds. While the primary structure of transglutaminases is not conserved, they all have the same amino acid sequence at their active sites and their activity is calcium-dependent. The protein encoded by this gene consists of two polypeptide chains activated from a single precursor protein by proteolysis. The encoded protein is involved the later stages of cell envelope formation in the epidermis and hair follicle. [provided by RefSeq, Jul 2008]

TGM3 Gene-Disease associations (from GenCC):

• uncombable hair syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• uncombable hair syndrome 2

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ENSG00000286022 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=5.7082315E-7).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.869 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003245.4. 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
	TGM3	NM_003245.4	MANE Select	c.1960G>C	p.Gly654Arg	missense	Exon 13 of 13	NP_003236.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGM3	ENST00000381458.6	TSL:1 MANE Select	c.1960G>C	p.Gly654Arg	missense	Exon 13 of 13	ENSP00000370867.5
	ENSG00000286022	ENST00000651531.1		c.2017G>C	p.Gly673Arg	missense	Exon 14 of 14	ENSP00000498584.1

Frequencies

GnomAD3 genomes AF: 0.722 AC: 109648 AN: 151810 Hom.: 40578 Cov.: 30

Gnomad AFR AF: 0.877

Gnomad AMI AF: 0.461

Gnomad AMR AF: 0.719

Gnomad ASJ AF: 0.516

Gnomad EAS AF: 0.855

Gnomad SAS AF: 0.780

Gnomad FIN AF: 0.721

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.630

Gnomad OTH AF: 0.704

GnomAD2 exomes AF: 0.709 AC: 177200 AN: 250082 AF XY: 0.705

Gnomad AFR exome AF: 0.885

Gnomad AMR exome AF: 0.761

Gnomad ASJ exome AF: 0.516

Gnomad EAS exome AF: 0.858

Gnomad FIN exome AF: 0.723

Gnomad NFE exome AF: 0.636

Gnomad OTH exome AF: 0.676

GnomAD4 exome AF: 0.659 AC: 962706 AN: 1461838 Hom.: 320938 Cov.: 70 AF XY: 0.661 AC XY: 480509 AN XY: 727220

African (AFR) AF: 0.889 AC: 29768 AN: 33480

American (AMR) AF: 0.757 AC: 33850 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.521 AC: 13613 AN: 26136

East Asian (EAS) AF: 0.865 AC: 34352 AN: 39700

South Asian (SAS) AF: 0.789 AC: 68075 AN: 86258

European-Finnish (FIN) AF: 0.718 AC: 38327 AN: 53410

Middle Eastern (MID) AF: 0.662 AC: 3820 AN: 5768

European-Non Finnish (NFE) AF: 0.630 AC: 700225 AN: 1111972

Other (OTH) AF: 0.674 AC: 40676 AN: 60392

GnomAD4 genome AF: 0.722 AC: 109744 AN: 151928 Hom.: 40619 Cov.: 30 AF XY: 0.728 AC XY: 54076 AN XY: 74256

African (AFR) AF: 0.877 AC: 36349 AN: 41466

American (AMR) AF: 0.719 AC: 10980 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.516 AC: 1787 AN: 3466

East Asian (EAS) AF: 0.855 AC: 4386 AN: 5132

South Asian (SAS) AF: 0.780 AC: 3743 AN: 4800

European-Finnish (FIN) AF: 0.721 AC: 7621 AN: 10576

Middle Eastern (MID) AF: 0.596 AC: 174 AN: 292

European-Non Finnish (NFE) AF: 0.630 AC: 42803 AN: 67914

Other (OTH) AF: 0.705 AC: 1481 AN: 2102

Alfa AF: 0.590 Hom.: 3269

Bravo AF: 0.728

TwinsUK AF: 0.626 AC: 2320

ALSPAC AF: 0.632 AC: 2437

ESP6500AA AF: 0.871 AC: 3838

ESP6500EA AF: 0.615 AC: 5289

ExAC AF: 0.712 AC: 86432

Asia WGS AF: 0.802 AC: 2785 AN: 3478

EpiCase AF: 0.621

EpiControl AF: 0.617

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	14
DANN	Benign	0.76
DEOGEN2	Benign	0.042	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.093	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	5.7e-7	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-2.4	N
PhyloP100		0.64
PrimateAI	Benign	0.27	T
PROVEAN	Benign	4.2	N
REVEL	Benign	0.098
Sift	Benign	1.0	T
Sift4G	Benign	0.99	T
Polyphen		0.0	B
Vest4		0.025
MutPred		0.14		Loss of ubiquitination at K652 (P = 0.0508)
MPC		0.094
ClinPred		0.0071	T
GERP RS		3.4
Varity_R		0.093
gMVP		0.31
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs214830; hg19: chr20-2321105; COSMIC: COSV67350665;