NM_000128.4:c.1378T>C

Variant names:

• chr4-186285711-T-C
• rs121965065
• NM_000128.4:c.1378T>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP2

The NM_000128.4(F11):​c.1378T>C​(p.Phe460Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F460V) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: F11 NM_000128.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.77
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• congenital factor XI deficiency

  Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-186285711-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 11895.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 47 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: 0.019886 (below the threshold of 3.09). Trascript score misZ: 0.83889 (below the threshold of 3.09). GenCC associations: The gene is linked to congenital factor XI deficiency.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000128.4. 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
	F11	NM_000128.4	MANE Select	c.1378T>C	p.Phe460Leu	missense	Exon 12 of 15	NP_000119.1
	F11	NM_001440590.1		c.1330T>C	p.Phe444Leu	missense	Exon 12 of 15	NP_001427519.1
	F11	NM_001440593.1		c.1378T>C	p.Phe460Leu	missense	Exon 12 of 14	NP_001427522.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F11	ENST00000403665.7	TSL:1 MANE Select	c.1378T>C	p.Phe460Leu	missense	Exon 12 of 15	ENSP00000384957.2
	F11	ENST00000264691.4	TSL:3	c.73T>C	p.Phe25Leu	missense	Exon 1 of 3	ENSP00000264691.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461820 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727198

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111962

Other (OTH) AF: 0.00 AC: 0 AN: 60386

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.086	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	-0.46	N
PhyloP100		2.8
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.59
Sift	Benign	0.13	T
Sift4G	Benign	0.11	T
Polyphen		1.0	D
Vest4		0.58
MutPred		0.61		Gain of glycosylation at S459 (P = 0.1672)
MVP		0.97
MPC		0.33
ClinPred		0.98	D
GERP RS		4.9
PromoterAI		-0.0022	Neutral
Varity_R		0.74
gMVP		0.76
Mutation Taster		=16/84	disease causing

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: rs121965065; hg19: chr4-187206865;