rs606231304

Variant names:

• chrX-77454154-T-TAGGAATCCTGGAGTTTATC
• rs606231304
• NM_003868.3:c.275_293dupGAATCCTGGAGTTTATCAG

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The ENST00000439435.3(FGF16):​c.275-3_275-2insAGGAATCCTGGAGTTTATC variant causes a splice acceptor, intron 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: 21)
  • Exomes 𝑓: 9.4e-7 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: FGF16 ENST00000439435.3 splice_acceptor, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.22
• Publications: 0 publications found

Genes affected

FGF16 (HGNC:3672): (fibroblast growth factor 16) This gene encodes a member of a family of proteins that are involved in a variety of biological processes, including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. This gene is expressed in cardiac cells and is required for proper heart development. Mutation in this gene was also observed in individuals with metacarpal 4-5 fusion. [provided by RefSeq, Mar 2014]

FGF16 Gene-Disease associations (from GenCC):

• syndactyly type 8

  Inheritance: AD, XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000295984 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 11, offset of -19, new splice context is: gtgttcactttttgccctAGgaa. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PP5: Variant X-77454154-T-TAGGAATCCTGGAGTTTATC is Pathogenic according to our data. Variant chrX-77454154-T-TAGGAATCCTGGAGTTTATC is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 160345.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000439435.3. 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
	FGF16	NM_003868.3	MANE Select	c.275_293dupGAATCCTGGAGTTTATCAG	p.Ser98fs	frameshift	Exon 2 of 3	NP_003859.1	O43320

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGF16	ENST00000439435.3	TSL:1 MANE Select	c.275-3_275-2insAGGAATCCTGGAGTTTATC		splice_acceptor intron	N/A	ENSP00000399324.2	O43320
	ENSG00000295984	ENST00000734738.1		n.179+7051_179+7052insGATAAACTCCAGGATTCCT		intron	N/A
	ENSG00000295984	ENST00000734739.1		n.45+7051_45+7052insGATAAACTCCAGGATTCCT		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.39e-7 AC: 1 AN: 1064937 Hom.: 0 Cov.: 25 AF XY: 0.00000298 AC XY: 1 AN XY: 335887

African (AFR) AF: 0.00 AC: 0 AN: 25729

American (AMR) AF: 0.00 AC: 0 AN: 34729

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19106

East Asian (EAS) AF: 0.00 AC: 0 AN: 29973

South Asian (SAS) AF: 0.00 AC: 0 AN: 52403

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40251

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4065

European-Non Finnish (NFE) AF: 0.00000123 AC: 1 AN: 813656

Other (OTH) AF: 0.00 AC: 0 AN: 45025

GnomAD4 genome Cov.: 21

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
1	-	-	Syndactyly type 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.2

Splicing

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

Other links and lift over

dbSNP: rs606231304; hg19: chrX-76709645;