chr5-177404118-A-G

Variant names:

• chr5-177404118-A-G
• rs17876031
• NM_000505.4:c.1019-28T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000505.4(F12):​c.1019-28T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.611 in 1,593,896 control chromosomes in the GnomAD database, including 306,615 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (24672 hom., cov: 34)
  • Exomes 𝑓: 0.62 (281943 hom.)
• Consequence: F12 NM_000505.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.01
• Publications: 15 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 5-177404118-A-G is Benign according to our data. Variant chr5-177404118-A-G is described in ClinVar as Benign. ClinVar VariationId is 1181607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.647 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F12	NM_000505.4	MANE Select	c.1019-28T>C		intron	N/A	NP_000496.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F12	ENST00000253496.4	TSL:1 MANE Select	c.1019-28T>C		intron	N/A	ENSP00000253496.3
	F12	ENST00000898128.1		c.1094-28T>C		intron	N/A	ENSP00000568187.1
	F12	ENST00000898127.1		c.1007-28T>C		intron	N/A	ENSP00000568186.1

Frequencies

GnomAD3 genomes AF: 0.553 AC: 84047 AN: 152022 Hom.: 24672 Cov.: 34

Gnomad AFR AF: 0.403

Gnomad AMI AF: 0.619

Gnomad AMR AF: 0.523

Gnomad ASJ AF: 0.714

Gnomad EAS AF: 0.225

Gnomad SAS AF: 0.428

Gnomad FIN AF: 0.690

Gnomad MID AF: 0.691

Gnomad NFE AF: 0.652

Gnomad OTH AF: 0.595

GnomAD2 exomes AF: 0.543 AC: 111107 AN: 204612 AF XY: 0.554

Gnomad AFR exome AF: 0.408

Gnomad AMR exome AF: 0.385

Gnomad ASJ exome AF: 0.713

Gnomad EAS exome AF: 0.230

Gnomad FIN exome AF: 0.677

Gnomad NFE exome AF: 0.659

Gnomad OTH exome AF: 0.596

GnomAD4 exome AF: 0.617 AC: 889922 AN: 1441756 Hom.: 281943 Cov.: 81 AF XY: 0.614 AC XY: 439852 AN XY: 716276

African (AFR) AF: 0.390 AC: 12969 AN: 33254

American (AMR) AF: 0.402 AC: 16789 AN: 41802

Ashkenazi Jewish (ASJ) AF: 0.714 AC: 18382 AN: 25760

East Asian (EAS) AF: 0.272 AC: 10645 AN: 39082

South Asian (SAS) AF: 0.451 AC: 38213 AN: 84636

European-Finnish (FIN) AF: 0.676 AC: 31711 AN: 46930

Middle Eastern (MID) AF: 0.639 AC: 3650 AN: 5714

European-Non Finnish (NFE) AF: 0.654 AC: 722113 AN: 1104932

Other (OTH) AF: 0.594 AC: 35450 AN: 59646

GnomAD4 genome AF: 0.552 AC: 84057 AN: 152140 Hom.: 24672 Cov.: 34 AF XY: 0.550 AC XY: 40926 AN XY: 74388

African (AFR) AF: 0.403 AC: 16732 AN: 41514

American (AMR) AF: 0.522 AC: 7974 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.714 AC: 2476 AN: 3468

East Asian (EAS) AF: 0.224 AC: 1154 AN: 5148

South Asian (SAS) AF: 0.428 AC: 2064 AN: 4826

European-Finnish (FIN) AF: 0.690 AC: 7321 AN: 10612

Middle Eastern (MID) AF: 0.682 AC: 199 AN: 292

European-Non Finnish (NFE) AF: 0.652 AC: 44323 AN: 67968

Other (OTH) AF: 0.592 AC: 1251 AN: 2114

Alfa AF: 0.638 Hom.: 14486

Bravo AF: 0.534

Asia WGS AF: 0.355 AC: 1237 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary angioedema type 3 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	9.6
DANN	Benign	0.42
PhyloP100		1.0
PromoterAI		-0.029	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: rs17876031; hg19: chr5-176831119;