X-77454154-T-TAGGAATCCTGGAGTTTATC

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 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. 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

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 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.
• PM2: Very rare variant in population databases, with high coverage
• 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 id is 160345.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGF16	NM_003868.3	c.275_293dupGAATCCTGGAGTTTATCAG	p.Ser98fs	frameshift_variant	Exon 2 of 3	ENST00000439435.3	NP_003859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGF16	ENST00000439435.3	c.275-3_275-2insAGGAATCCTGGAGTTTATC		splice_acceptor_variant, intron_variant	Intron 1 of 2	1	NM_003868.3	ENSP00000399324.2

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

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000123

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Syndactyly type 8 Pathogenic:1

Jul 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Aug 14, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in abnormal protein length as the last 110 amino acids are replaced with 27 different amino acids; This variant is associated with the following publications: (PMID: 24878828) -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs606231304; hg19: chrX-76709645;