chr1-197050892-G-T

Variant names:

• chr1-197050892-G-T
• rs149088047
• NM_001994.3:c.1556-13C>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001994.3(F13B):​c.1556-13C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00145 in 1,607,192 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (16 hom.)
• Consequence: F13B NM_001994.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.315
• Publications: 0 publications found

Genes affected

F13B (HGNC:3534): (coagulation factor XIII B chain) This gene encodes coagulation factor XIII B 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 a plasma carrier molecules. Platelet factor XIII is comprised only of 2 A subunits, which are identical to those of plasma origin. Upon activation by the 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. 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]

F13B Gene-Disease associations (from GenCC):

• factor XIII, b subunit, deficiency of

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• congenital factor XIII deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 1-197050892-G-T is Benign according to our data. Variant chr1-197050892-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 258503.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00108 (164/152270) while in subpopulation SAS AF = 0.0122 (59/4828). AF 95% confidence interval is 0.00973. There are 3 homozygotes in GnomAd4. There are 99 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F13B	NM_001994.3	c.1556-13C>A		intron_variant	Intron 9 of 11	ENST00000367412.2	NP_001985.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F13B	ENST00000367412.2	c.1556-13C>A		intron_variant	Intron 9 of 11	1	NM_001994.3	ENSP00000356382.2
F13B	ENST00000649282.1	c.311-13C>A		intron_variant	Intron 2 of 4			ENSP00000497116.1
F13B	ENST00000490002.1	n.-47C>A		upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00107 AC: 163 AN: 152152 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0120

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00231 AC: 574 AN: 248876 AF XY: 0.00289

Gnomad AFR exome AF: 0.0000621

Gnomad AMR exome AF: 0.000350

Gnomad ASJ exome AF: 0.00789

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.0000936

Gnomad NFE exome AF: 0.00114

Gnomad OTH exome AF: 0.00231

GnomAD4 exome AF: 0.00149 AC: 2162 AN: 1454922 Hom.: 16 Cov.: 28 AF XY: 0.00182 AC XY: 1320 AN XY: 724160

African (AFR) AF: 0.000120 AC: 4 AN: 33304

American (AMR) AF: 0.000337 AC: 15 AN: 44550

Ashkenazi Jewish (ASJ) AF: 0.00841 AC: 219 AN: 26044

East Asian (EAS) AF: 0.00 AC: 0 AN: 39574

South Asian (SAS) AF: 0.0108 AC: 927 AN: 86046

European-Finnish (FIN) AF: 0.000113 AC: 6 AN: 53006

Middle Eastern (MID) AF: 0.00785 AC: 45 AN: 5732

European-Non Finnish (NFE) AF: 0.000741 AC: 820 AN: 1106596

Other (OTH) AF: 0.00210 AC: 126 AN: 60070

GnomAD4 genome AF: 0.00108 AC: 164 AN: 152270 Hom.: 3 Cov.: 32 AF XY: 0.00133 AC XY: 99 AN XY: 74444

African (AFR) AF: 0.0000962 AC: 4 AN: 41564

American (AMR) AF: 0.000262 AC: 4 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.0122 AC: 59 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00104 AC: 71 AN: 68020

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00114 Hom.: 0

Bravo AF: 0.000744

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Factor XIII, b subunit, deficiency of Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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 specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	8.5
DANN	Benign	0.67
PhyloP100		-0.32
Mutation Taster		=100/0	polymorphism

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: rs149088047; hg19: chr1-197020022;