NM_000505.4:c.1342C>T

Variant names:

• chr5-177403526-G-A
• rs115119084
• NM_000505.4:c.1342C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000505.4(F12):​c.1342C>T​(p.Arg448Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,587,578 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R448H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0063 (13 hom., cov: 33)
  • Exomes 𝑓: 0.00057 (9 hom.)
• Consequence: F12 NM_000505.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.00600
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009305).
• BP6: Variant 5-177403526-G-A is Benign according to our data. Variant chr5-177403526-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 352986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00635 (967/152352) while in subpopulation AFR AF = 0.0216 (899/41592). AF 95% confidence interval is 0.0204. There are 13 homozygotes in GnomAd4. There are 445 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AR,AD gene

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.1342C>T	p.Arg448Cys	missense	Exon 11 of 14	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.1342C>T	p.Arg448Cys	missense	Exon 11 of 14	ENSP00000253496.3	P00748
	F12	ENST00000898128.1		c.1417C>T	p.Arg473Cys	missense	Exon 12 of 15	ENSP00000568187.1
	F12	ENST00000898127.1		c.1330C>T	p.Arg444Cys	missense	Exon 10 of 13	ENSP00000568186.1

Frequencies

GnomAD3 genomes AF: 0.00633 AC: 964 AN: 152236 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.0216

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

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: 0.000118

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00139 AC: 287 AN: 206098 AF XY: 0.000938

Gnomad AFR exome AF: 0.0205

Gnomad AMR exome AF: 0.000852

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000647

Gnomad OTH exome AF: 0.00113

GnomAD4 exome AF: 0.000574 AC: 824 AN: 1435226 Hom.: 9 Cov.: 31 AF XY: 0.000490 AC XY: 349 AN XY: 712800

African (AFR) AF: 0.0199 AC: 656 AN: 32926

American (AMR) AF: 0.00104 AC: 43 AN: 41376

Ashkenazi Jewish (ASJ) AF: 0.0000389 AC: 1 AN: 25684

East Asian (EAS) AF: 0.00 AC: 0 AN: 38278

South Asian (SAS) AF: 0.0000719 AC: 6 AN: 83490

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45848

Middle Eastern (MID) AF: 0.000885 AC: 5 AN: 5650

European-Non Finnish (NFE) AF: 0.0000336 AC: 37 AN: 1102436

Other (OTH) AF: 0.00128 AC: 76 AN: 59538

GnomAD4 genome AF: 0.00635 AC: 967 AN: 152352 Hom.: 13 Cov.: 33 AF XY: 0.00597 AC XY: 445 AN XY: 74502

African (AFR) AF: 0.0216 AC: 899 AN: 41592

American (AMR) AF: 0.00320 AC: 49 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68028

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00142 Hom.: 2

Bravo AF: 0.00712

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0202 AC: 88

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00173 AC: 208

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	F12-related disorder (1)
-	-	1	Factor XII deficiency disease (1)
-	-	1	Hereditary angioedema type 3 (1)
-	-	1	Hereditary angioneurotic edema (1)
-	-	1	Nephrolithiasis/osteoporosis, hypophosphatemic (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0093	T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.0060
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.44
Sift	Benign	0.058	T
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.52
MVP		0.93
MPC		2.1
ClinPred		0.029	T
GERP RS		3.4
PromoterAI		0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.40
gMVP		0.80
Mutation Taster		=91/9	polymorphism

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: rs115119084; hg19: chr5-176830527;