rs214803

Variant names:

• chr20-2309687-C-A
• rs214803
• NM_003245.4:c.38C>A

Your query was ambiguous. Multiple possible variants found:

• chr20-2309687-C-A
• chr20-2309687-C-G
• chr20-2309687-C-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_003245.4(TGM3):​c.38C>A​(p.Thr13Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.81 in 1,613,856 control chromosomes in the GnomAD database, including 535,774 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.73 (42987 hom., cov: 32)
  • Exomes 𝑓: 0.82 (492787 hom.)
• Consequence: TGM3 NM_003245.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -2.43
• Publications: 37 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.677294E-7).
• BP6: Variant 20-2309687-C-A is Benign according to our data. Variant chr20-2309687-C-A is described in ClinVar as Benign. ClinVar VariationId is 3060440.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.912 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGM3	NM_003245.4	MANE Select	c.38C>A	p.Thr13Lys	missense	Exon 2 of 13	NP_003236.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGM3	ENST00000381458.6	TSL:1 MANE Select	c.38C>A	p.Thr13Lys	missense	Exon 2 of 13	ENSP00000370867.5
	ENSG00000286022	ENST00000651531.1		c.95C>A	p.Thr32Lys	missense	Exon 3 of 14	ENSP00000498584.1

Frequencies

GnomAD3 genomes AF: 0.734 AC: 111525 AN: 151970 Hom.: 42964 Cov.: 32

Gnomad AFR AF: 0.471

Gnomad AMI AF: 0.845

Gnomad AMR AF: 0.838

Gnomad ASJ AF: 0.792

Gnomad EAS AF: 0.934

Gnomad SAS AF: 0.840

Gnomad FIN AF: 0.859

Gnomad MID AF: 0.709

Gnomad NFE AF: 0.823

Gnomad OTH AF: 0.756

GnomAD2 exomes AF: 0.819 AC: 205989 AN: 251430 AF XY: 0.823

Gnomad AFR exome AF: 0.462

Gnomad AMR exome AF: 0.893

Gnomad ASJ exome AF: 0.779

Gnomad EAS exome AF: 0.933

Gnomad FIN exome AF: 0.863

Gnomad NFE exome AF: 0.821

Gnomad OTH exome AF: 0.804

GnomAD4 exome AF: 0.818 AC: 1196237 AN: 1461768 Hom.: 492787 Cov.: 67 AF XY: 0.819 AC XY: 595705 AN XY: 727182

African (AFR) AF: 0.455 AC: 15235 AN: 33476

American (AMR) AF: 0.887 AC: 39648 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.780 AC: 20377 AN: 26132

East Asian (EAS) AF: 0.946 AC: 37542 AN: 39700

South Asian (SAS) AF: 0.835 AC: 72029 AN: 86256

European-Finnish (FIN) AF: 0.859 AC: 45903 AN: 53420

Middle Eastern (MID) AF: 0.729 AC: 4172 AN: 5722

European-Non Finnish (NFE) AF: 0.821 AC: 912836 AN: 1111948

Other (OTH) AF: 0.803 AC: 48495 AN: 60390

GnomAD4 genome AF: 0.734 AC: 111603 AN: 152088 Hom.: 42987 Cov.: 32 AF XY: 0.740 AC XY: 55046 AN XY: 74352

African (AFR) AF: 0.471 AC: 19514 AN: 41440

American (AMR) AF: 0.839 AC: 12818 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.792 AC: 2747 AN: 3470

East Asian (EAS) AF: 0.934 AC: 4825 AN: 5166

South Asian (SAS) AF: 0.839 AC: 4051 AN: 4826

European-Finnish (FIN) AF: 0.859 AC: 9104 AN: 10598

Middle Eastern (MID) AF: 0.707 AC: 208 AN: 294

European-Non Finnish (NFE) AF: 0.823 AC: 55964 AN: 67984

Other (OTH) AF: 0.758 AC: 1601 AN: 2112

Alfa AF: 0.793 Hom.: 199322

Bravo AF: 0.720

TwinsUK AF: 0.821 AC: 3044

ALSPAC AF: 0.822 AC: 3169

ESP6500AA AF: 0.485 AC: 2137

ESP6500EA AF: 0.821 AC: 7058

ExAC AF: 0.810 AC: 98372

Asia WGS AF: 0.877 AC: 3052 AN: 3478

EpiCase AF: 0.813

EpiControl AF: 0.806

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	TGM3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.0080
DANN	Benign	0.44
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.10	T
MetaRNN	Benign	9.7e-7	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.69	N
PhyloP100		-2.4
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.17
Sift	Benign	0.69	T
Sift4G	Benign	0.64	T
Polyphen		0.73	P
Vest4		0.037
MPC		0.096
ClinPred		0.0052	T
GERP RS		-1.1
Varity_R		0.17
gMVP		0.42
Mutation Taster		=94/6	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: rs214803; hg19: chr20-2290333; COSMIC: COSV67350838; COSMIC: COSV67350838;