4-186271680-G-A

Position:

• chr4-186271680-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PS1_Moderate PM1 PM2

The NM_000128.4(F11):​c.127G>A​(p.Ala43Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: F11 NM_000128.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 1.98

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PS1: Transcript NM_000128.4 (F11) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a helix (size 9) in uniprot entity FA11_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_000128.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F11	NM_000128.4	c.127G>A	p.Ala43Thr	missense_variant	3/15	ENST00000403665.7	NP_000119.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F11	ENST00000403665.7	c.127G>A	p.Ala43Thr	missense_variant	3/15	1	NM_000128.4	ENSP00000384957.2
F11	ENST00000492972.6	c.127G>A	p.Ala43Thr	missense_variant	3/5	2		ENSP00000424479.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000358 AC: 9 AN: 251460 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135900

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461858 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 28, 2024

Variant summary: F11 c.127G>A (p.Ala43Thr) results in a non-conservative amino acid change located in the Apple domain (IPR000177) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251460 control chromosomes. c.127G>A has been reported in the literature as heterozygous or compound heterozygous genotype in individuals affected with Hereditary factor XI deficiency disease with no detailed clinical presentations or segregation data (Rugeri_2010, Dai_2011). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary factor XI deficiency disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 76% reduction of extracellular F11 secretion (Dai_2011). The following publications have been ascertained in the context of this evaluation (PMID: 21457405, 20398070). ClinVar contains an entry for this variant (Variation ID: 68174). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

not provided Other:1

not provided, no classification provided

literature only

UniProtKB/Swiss-Prot

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;D;.
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.21	N
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Uncertain	0.090	D
MetaRNN	Uncertain	0.44	T;T;T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Uncertain	2.6	M;.;M
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Uncertain	0.38
Sift	Uncertain	0.0070	D;T;D
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.30
MutPred		0.72		Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);
MVP		0.99
MPC		0.17
ClinPred		0.17	T
GERP RS		3.5
Varity_R		0.38
gMVP		0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs281875264; hg19: chr4-187192834;