rs281875263

chr4-186287685-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000128.4(F11):c.1578C>G(p.Asp526Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000117 in 1,457,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as not provided (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: F11 NM_000128.4 missense, splice_region
• Scores: Splicing: ADA: 0.0002754
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: -0.132

Genes affected

F11 (HGNC:3529): (coagulation factor XI) This gene encodes coagulation factor XI of the blood coagulation cascade. This protein is present in plasma as a zymogen, which is a unique plasma coagulation enzyme because it exists as a homodimer consisting of two identical polypeptide chains linked by disulfide bonds. During activation of the plasma factor XI, an internal peptide bond is cleaved by factor XIIa (or XII) in each of the two chains, resulting in activated factor XIa, a serine protease composed of two heavy and two light chains held together by disulfide bonds. This activated plasma factor XI triggers the middle phase of the intrisic pathway of blood coagulation by activating factor IX. Defects in this factor lead to Rosenthal syndrome, a blood coagulation abnormality. [provided by RefSeq, Jul 2008]

F11-AS1 (HGNC:27725): (F11 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a disulfide_bond (size 67) in uniprot entity FA11_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_000128.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27858514).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F11	NM_000128.4	c.1578C>G	p.Asp526Glu	missense_variant, splice_region_variant	14/15	ENST00000403665.7
F11-AS1	NR_033900.1	n.1066+743G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F11	ENST00000403665.7	c.1578C>G	p.Asp526Glu	missense_variant, splice_region_variant	14/15	1	NM_000128.4	P1
F11-AS1	ENST00000505103.5	n.1005+743G>C		intron_variant, non_coding_transcript_variant		1
F11	ENST00000264691.4	c.180C>G	p.Asp60Glu	missense_variant, splice_region_variant	2/3	3
F11	ENST00000503841.1	n.97C>G		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000799 AC: 2 AN: 250446 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135424

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000117 AC: 17 AN: 1457660 Hom.: 0 Cov.: 31 AF XY: 0.00000965 AC XY: 7 AN XY: 725204

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000228

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome Cov.: 30

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

not provided, no classification provided

literature only

UniProtKB/Swiss-Prot

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Uncertain	-0.040
Cadd	Benign	13
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T;.
Eigen	Benign	0.039
Eigen_PC	Benign	-0.039
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.61	T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.64	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.1	N;.
REVEL	Uncertain	0.56
Sift	Uncertain	0.0020	D;.
Sift4G	Benign	0.068	T;T
Polyphen		0.023	B;.
Vest4		0.21
MutPred		0.47		Gain of methylation at K523 (P = 0.0807);.;
MVP		0.96
MPC		0.092
ClinPred		0.25	T
GERP RS		2.7
Varity_R		0.52
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00028
dbscSNV1_RF	Benign	0.040
SpliceAI score (max)		0.090		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: rs281875263; hg19: chr4-187208839;