5-177404979-T-C

Variant names:

• chr5-177404979-T-C
• rs17876029
• NM_000505.4:c.530-65A>G

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.530-65A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.977 in 1,588,580 control chromosomes in the GnomAD database, including 759,476 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.97 (70972 hom., cov: 31)
  • Exomes 𝑓: 0.98 (688504 hom.)
• Consequence: F12 NM_000505.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.85
• Publications: 5 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=-0.88).
• BP6: Variant 5-177404979-T-C is Benign according to our data. Variant chr5-177404979-T-C is described in ClinVar as Benign. ClinVar VariationId is 1249273.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.982 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.530-65A>G		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.530-65A>G		intron	N/A	ENSP00000253496.3
	F12	ENST00000898128.1		c.605-65A>G		intron	N/A	ENSP00000568187.1
	F12	ENST00000898127.1		c.573-65A>G		intron	N/A	ENSP00000568186.1

Frequencies

GnomAD3 genomes AF: 0.965 AC: 146749 AN: 152034 Hom.: 70934 Cov.: 31

Gnomad AFR AF: 0.960

Gnomad AMI AF: 0.882

Gnomad AMR AF: 0.887

Gnomad ASJ AF: 0.990

Gnomad EAS AF: 0.899

Gnomad SAS AF: 0.955

Gnomad FIN AF: 0.989

Gnomad MID AF: 0.987

Gnomad NFE AF: 0.988

Gnomad OTH AF: 0.967

GnomAD4 exome AF: 0.979 AC: 1405651 AN: 1436428 Hom.: 688504 Cov.: 50 AF XY: 0.979 AC XY: 698510 AN XY: 713848

African (AFR) AF: 0.956 AC: 31718 AN: 33182

American (AMR) AF: 0.828 AC: 34540 AN: 41720

Ashkenazi Jewish (ASJ) AF: 0.987 AC: 25409 AN: 25754

East Asian (EAS) AF: 0.915 AC: 35777 AN: 39080

South Asian (SAS) AF: 0.958 AC: 81042 AN: 84598

European-Finnish (FIN) AF: 0.989 AC: 42213 AN: 42674

Middle Eastern (MID) AF: 0.964 AC: 5542 AN: 5750

European-Non Finnish (NFE) AF: 0.988 AC: 1091261 AN: 1103988

Other (OTH) AF: 0.974 AC: 58149 AN: 59682

GnomAD4 genome AF: 0.965 AC: 146841 AN: 152152 Hom.: 70972 Cov.: 31 AF XY: 0.963 AC XY: 71628 AN XY: 74380

African (AFR) AF: 0.960 AC: 39861 AN: 41520

American (AMR) AF: 0.886 AC: 13540 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.990 AC: 3436 AN: 3472

East Asian (EAS) AF: 0.898 AC: 4620 AN: 5144

South Asian (SAS) AF: 0.955 AC: 4607 AN: 4822

European-Finnish (FIN) AF: 0.989 AC: 10490 AN: 10606

Middle Eastern (MID) AF: 0.986 AC: 290 AN: 294

European-Non Finnish (NFE) AF: 0.988 AC: 67161 AN: 67992

Other (OTH) AF: 0.964 AC: 2033 AN: 2110

Alfa AF: 0.975 Hom.: 9701

Bravo AF: 0.956

Asia WGS AF: 0.926 AC: 3223 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	-0.88
CADD	Benign	0.23
DANN	Benign	0.52
PhyloP100		-3.9
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: rs17876029; hg19: chr5-176831980;