NM_000504.4:c.183_184delCTinsTTGCTCATACGAAGAGGCCC

Variant names:

• chr13-113129564-CT-TTGCTCATACGAAGAGGCCC
• NM_000504.4:c.183_184delCTinsTTGCTCATACGAAGAGGCCC

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM4 PP3 PP5_Moderate

The NM_000504.4(F10):​c.183_184delCTinsTTGCTCATACGAAGAGGCCC​(p.Cys62_Ser63insSerTyrGluGluAlaArg) variant causes a conservative inframe insertion, synonymous change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: F10 NM_000504.4 conservative_inframe_insertion, synonymous
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.86
• Publications: 0 publications found

Genes affected

F10 (HGNC:3528): (coagulation factor X) This gene encodes the vitamin K-dependent coagulation factor X of the blood coagulation cascade. This factor undergoes multiple processing steps before its preproprotein is converted to a mature two-chain form by the excision of the tripeptide RKR. Two chains of the factor are held together by 1 or more disulfide bonds; the light chain contains 2 EGF-like domains, while the heavy chain contains the catalytic domain which is structurally homologous to those of the other hemostatic serine proteases. The mature factor is activated by the cleavage of the activation peptide by factor IXa (in the intrisic pathway), or by factor VIIa (in the extrinsic pathway). The activated factor then converts prothrombin to thrombin in the presence of factor Va, Ca+2, and phospholipid during blood clotting. Mutations of this gene result in factor X deficiency, a hemorrhagic condition of variable severity. Alternative splicing results in multiple transcript variants encoding different isoforms that may undergo similar proteolytic processing to generate mature polypeptides. [provided by RefSeq, Aug 2015]

F10-AS1 (HGNC:40225): (F10 antisense RNA 1)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000504.4
• PM4: Nonframeshift variant in NON repetitive region in NM_000504.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 13-113129564-CT-TTGCTCATACGAAGAGGCCC is Pathogenic according to our data. Variant chr13-113129564-CT-TTGCTCATACGAAGAGGCCC is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3575773.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000504.4. 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
	F10	NM_000504.4	MANE Select	c.183_184delCTinsTTGCTCATACGAAGAGGCCC	p.Cys62_Ser63insSerTyrGluGluAlaArg	conservative_inframe_insertion synonymous	Exon 2 of 8	NP_000495.1	Q5JVE7
	F10	NM_001312674.2		c.183_184delCTinsTTGCTCATACGAAGAGGCCC	p.Cys62_Ser63insSerTyrGluGluAlaArg	conservative_inframe_insertion synonymous	Exon 2 of 7	NP_001299603.1
	F10	NM_001312675.2		c.183_184delCTinsTTGCTCATACGAAGAGGCCC	p.Cys62_Ser63insSerTyrGluGluAlaArg	conservative_inframe_insertion synonymous	Exon 2 of 8	NP_001299604.1	Q5JVE8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F10	ENST00000375559.8	TSL:1 MANE Select	c.183_184delCTinsTTGCTCATACGAAGAGGCCC	p.Cys62_Ser63insSerTyrGluGluAlaArg	conservative_inframe_insertion synonymous	Exon 2 of 8	ENSP00000364709.3	P00742
	F10	ENST00000375551.7	TSL:1	c.183_184delCTinsTTGCTCATACGAAGAGGCCC	p.Cys62_Ser63insSerTyrGluGluAlaArg	conservative_inframe_insertion synonymous	Exon 2 of 8	ENSP00000364701.3	Q5JVE8
	F10	ENST00000410083.6	TSL:1	n.183_184delCTinsTTGCTCATACGAAGAGGCCC		non_coding_transcript_exon	Exon 2 of 7	ENSP00000386320.2	F8WBM7

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Hereditary factor X deficiency disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9

Splicing

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

Other links and lift over

hg19: chr13-113783878;