NM_000129.4:c.1748-2039A>C

Variant names:

• chr6-6169657-T-G
• rs6934608
• NM_000129.4:c.1748-2039A>C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000129.4(F13A1):​c.1748-2039A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0858 in 152,172 control chromosomes in the GnomAD database, including 735 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.086 (735 hom., cov: 32)
• Consequence: F13A1 NM_000129.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.114

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]

MIR7853 (HGNC:49933): (microRNA 7853) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

MIR5683 (HGNC:43453): (microRNA 5683) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F13A1	NM_000129.4	c.1748-2039A>C		intron_variant	Intron 12 of 14	ENST00000264870.8	NP_000120.2
MIR7853	NR_107007.1	n.-222A>C		upstream_gene_variant
MIR5683	NR_049863.1	n.*248T>G		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F13A1	ENST00000264870.8	c.1748-2039A>C		intron_variant	Intron 12 of 14	1	NM_000129.4	ENSP00000264870.3
MIR7853	ENST00000584820.2	n.-222A>C		upstream_gene_variant		6
MIR5683	ENST00000636514.1	n.*248T>G		downstream_gene_variant		6

Frequencies

GnomAD3 genomes AF: 0.0856 AC: 13019 AN: 152054 Hom.: 726 Cov.: 32

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0665

Gnomad ASJ AF: 0.0314

Gnomad EAS AF: 0.0224

Gnomad SAS AF: 0.0244

Gnomad FIN AF: 0.0430

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0704

Gnomad OTH AF: 0.0781

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0858 AC: 13056 AN: 152172 Hom.: 735 Cov.: 32 AF XY: 0.0838 AC XY: 6237 AN XY: 74404

Gnomad4 AFR AF: 0.150

Gnomad4 AMR AF: 0.0664

Gnomad4 ASJ AF: 0.0314

Gnomad4 EAS AF: 0.0222

Gnomad4 SAS AF: 0.0245

Gnomad4 FIN AF: 0.0430

Gnomad4 NFE AF: 0.0704

Gnomad4 OTH AF: 0.0777

Alfa AF: 0.0784 Hom.: 66

Bravo AF: 0.0920

Asia WGS AF: 0.0310 AC: 110 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	4.3
DANN	Benign	0.89

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

Other links and lift over

dbSNP: rs6934608; hg19: chr6-6169890;