rs767240420

Variant names:

• chr4-186271775-A-G
• rs767240420
• NM_000128.4:c.218+4A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_000128.4(F11):​c.218+4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: F11 NM_000128.4 splice_region, intron
• Scores: Splicing: ADA: 0.9663
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 3.06

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 4-186271775-A-G is Pathogenic according to our data. Variant chr4-186271775-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 488986.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F11	NM_000128.4	c.218+4A>G		splice_region_variant, intron_variant	Intron 3 of 14	ENST00000403665.7	NP_000119.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F11	ENST00000403665.7	c.218+4A>G		splice_region_variant, intron_variant	Intron 3 of 14	1	NM_000128.4	ENSP00000384957.2
F11	ENST00000492972.6	c.218+4A>G		splice_region_variant, intron_variant	Intron 3 of 4	2		ENSP00000424479.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251430 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135892

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461840 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary factor XI deficiency disease Pathogenic:1 Uncertain:1

Jun 23, 2023

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The homozygous c.218+4A>G intronic variant has been identified in a proband with low factor XI levels and has shown prolonged activated partial thromboplastin time. This variant has been observed in 0.0004% gnomAD (aggregated) database (PM2_Moderate). Splice site predictors have predicted to cause deleterious effect (PP3_moderate). PMID: 27710856 has reported this variant previously in 2016. -

Aug 08, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Dec 07, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.218+4A>G variant in the F11 gene has been reported previously in association with factor XI deficiency, in affected individuals who homozygous or heterozygous for the c.218+4A>G variant (Kawankar et al., 2016). This variant reduces the quality of the splice donor site in intron 3, and is expected to cause abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of c.218+4A>G in this individual is unknown. The c.218+4A>G variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.218+4A>G as a variant of uncertain significance. -

Plasma factor XI deficiency Uncertain:1

Mar 03, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	7.0
DANN	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.85
SpliceAI score (max)		0.58		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.58		Position offset: -4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs767240420; hg19: chr4-187192929;