rs79281364

Variant names:

• chr5-177403432-G-A
• rs79281364
• NM_000505.4:c.1388-35C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000505.4(F12):​c.1388-35C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00284 in 1,569,144 control chromosomes in the GnomAD database, including 134 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.015 (72 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (62 hom.)
• Consequence: F12 NM_000505.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.665
• Publications: 0 publications found

Genes affected

F12 (HGNC:3530): (coagulation factor XII) This gene encodes coagulation factor XII which circulates in blood as a zymogen. This single chain zymogen is converted to a two-chain serine protease with an heavy chain (alpha-factor XIIa) and a light chain. The heavy chain contains two fibronectin-type domains, two epidermal growth factor (EGF)-like domains, a kringle domain and a proline-rich domain, whereas the light chain contains only a catalytic domain. On activation, further cleavages takes place in the heavy chain, resulting in the production of beta-factor XIIa light chain and the alpha-factor XIIa light chain becomes beta-factor XIIa heavy chain. Prekallikrein is cleaved by factor XII to form kallikrein, which then cleaves factor XII first to alpha-factor XIIa and then to beta-factor XIIa. The active factor XIIa participates in the initiation of blood coagulation, fibrinolysis, and the generation of bradykinin and angiotensin. It activates coagulation factors VII and XI. Defects in this gene do not cause any clinical symptoms and the sole effect is that whole-blood clotting time is prolonged. [provided by RefSeq, Jul 2008]

GRK6 (HGNC:4545): (G protein-coupled receptor kinase 6) This gene encodes a member of the guanine nucleotide-binding protein (G protein)-coupled receptor kinase subfamily of the Ser/Thr protein kinase family. The protein phosphorylates the activated forms of G protein-coupled receptors thus initiating their deactivation. Several transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 5-177403432-G-A is Benign according to our data. Variant chr5-177403432-G-A is described in ClinVar as Benign. ClinVar VariationId is 1252406.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0521 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000505.4. 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
	F12	NM_000505.4	MANE Select	c.1388-35C>T		intron	N/A	NP_000496.2	P00748

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F12	ENST00000253496.4	TSL:1 MANE Select	c.1388-35C>T		intron	N/A	ENSP00000253496.3	P00748
	GRK6	ENST00000502598.5	TSL:4	c.-139G>A		5_prime_UTR	Exon 1 of 4	ENSP00000422873.1	D6R9V4
	F12	ENST00000898128.1		c.1463-35C>T		intron	N/A	ENSP00000568187.1

Frequencies

GnomAD3 genomes AF: 0.0153 AC: 2323 AN: 152198 Hom.: 72 Cov.: 33

Gnomad AFR AF: 0.0541

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00716

GnomAD2 exomes AF: 0.00344 AC: 614 AN: 178408 AF XY: 0.00249

Gnomad AFR exome AF: 0.0533

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000770

Gnomad OTH exome AF: 0.000828

GnomAD4 exome AF: 0.00151 AC: 2134 AN: 1416828 Hom.: 62 Cov.: 31 AF XY: 0.00132 AC XY: 930 AN XY: 702652

African (AFR) AF: 0.0559 AC: 1825 AN: 32674

American (AMR) AF: 0.00221 AC: 87 AN: 39300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25492

East Asian (EAS) AF: 0.00 AC: 0 AN: 37612

South Asian (SAS) AF: 0.000144 AC: 12 AN: 83316

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38128

Middle Eastern (MID) AF: 0.00140 AC: 8 AN: 5718

European-Non Finnish (NFE) AF: 0.0000292 AC: 32 AN: 1095568

Other (OTH) AF: 0.00288 AC: 170 AN: 59020

GnomAD4 genome AF: 0.0153 AC: 2323 AN: 152316 Hom.: 72 Cov.: 33 AF XY: 0.0146 AC XY: 1086 AN XY: 74488

African (AFR) AF: 0.0540 AC: 2243 AN: 41570

American (AMR) AF: 0.00359 AC: 55 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68014

Other (OTH) AF: 0.00709 AC: 15 AN: 2116

Alfa AF: 0.00827 Hom.: 6

Bravo AF: 0.0174

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	5.7
DANN	Benign	0.84
PhyloP100		-0.67
PromoterAI		-0.011	Neutral
Mutation Taster		=100/0	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: rs79281364; hg19: chr5-176830433;