6-6144574-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_000129.4(F13A1):​c.*1045C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0214 in 152,232 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.021 ( 48 hom., cov: 31)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

F13A1
NM_000129.4 3_prime_UTR

Scores

2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.144
Variant links:
Genes affected
F13A1 (HGNC:3531): (coagulation factor XIII A chain) This gene encodes the coagulation factor XIII A subunit. Coagulation factor XIII is the last zymogen to become activated in the blood coagulation cascade. Plasma factor XIII is a heterotetramer composed of 2 A subunits and 2 B subunits. The A subunits have catalytic function, and the B subunits do not have enzymatic activity and may serve as plasma carrier molecules. Platelet factor XIII is comprised only of 2 A subunits, which are identical to those of plasma origin. Upon cleavage of the activation peptide by thrombin and in the presence of calcium ion, the plasma factor XIII dissociates its B subunits and yields the same active enzyme, factor XIIIa, as platelet factor XIII. This enzyme acts as a transglutaminase to catalyze the formation of gamma-glutamyl-epsilon-lysine crosslinking between fibrin molecules, thus stabilizing the fibrin clot. It also crosslinks alpha-2-plasmin inhibitor, or fibronectin, to the alpha chains of fibrin. Factor XIII deficiency is classified into two categories: type I deficiency, characterized by the lack of both the A and B subunits; and type II deficiency, characterized by the lack of the A subunit alone. These defects can result in a lifelong bleeding tendency, defective wound healing, and habitual abortion. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.86).
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0214 (3263/152232) while in subpopulation NFE AF= 0.0333 (2262/68020). AF 95% confidence interval is 0.0321. There are 48 homozygotes in gnomad4. There are 1581 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAd4 at 48 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
F13A1NM_000129.4 linkuse as main transcriptc.*1045C>G 3_prime_UTR_variant 15/15 ENST00000264870.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
F13A1ENST00000264870.8 linkuse as main transcriptc.*1045C>G 3_prime_UTR_variant 15/151 NM_000129.4 P1

Frequencies

GnomAD3 genomes
AF:
0.0215
AC:
3264
AN:
152114
Hom.:
48
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00545
Gnomad AMI
AF:
0.00219
Gnomad AMR
AF:
0.0122
Gnomad ASJ
AF:
0.0323
Gnomad EAS
AF:
0.000386
Gnomad SAS
AF:
0.0259
Gnomad FIN
AF:
0.0271
Gnomad MID
AF:
0.0475
Gnomad NFE
AF:
0.0332
Gnomad OTH
AF:
0.0225
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
26
Hom.:
0
Cov.:
0
AF XY:
0.00
AC XY:
0
AN XY:
10
Gnomad4 AFR exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
GnomAD4 genome
AF:
0.0214
AC:
3263
AN:
152232
Hom.:
48
Cov.:
31
AF XY:
0.0212
AC XY:
1581
AN XY:
74404
show subpopulations
Gnomad4 AFR
AF:
0.00541
Gnomad4 AMR
AF:
0.0122
Gnomad4 ASJ
AF:
0.0323
Gnomad4 EAS
AF:
0.000387
Gnomad4 SAS
AF:
0.0260
Gnomad4 FIN
AF:
0.0271
Gnomad4 NFE
AF:
0.0333
Gnomad4 OTH
AF:
0.0223
Alfa
AF:
0.0272
Hom.:
16
Bravo
AF:
0.0194
Asia WGS
AF:
0.0140
AC:
48
AN:
3476

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Factor XIII, A subunit, deficiency of Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.86
CADD
Benign
5.7
DANN
Benign
0.76

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.

Other links and lift over

dbSNP: rs3024487; hg19: chr6-6144807; API