dbSNP rs606231304: FGF16:p.Ser98fs (chrX-77454154-T-TAGGAATCCTGGAGTTTATC) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PP5_Moderate

The NM_003868.3(FGF16):c.275_293dupGAATCCTGGAGTTTATCAG(p.Ser98fs) variant causes a frameshift 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 (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 21)

Exomes 𝑓: 9.4e-7 ( 0 hom. 1 hem. )

Failed GnomAD Quality Control

Consequence

FGF16
NM_003868.3 frameshift

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 9.22

Publications

0 publications found

Variant links:

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)

FGF16 links:

ENSG00000295984 (HGNC:):

ENSG00000295984 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGF16	NM_003868.3 link	c.275_293dupGAATCCTGGAGTTTATCAG	p.Ser98fs	frameshift_variant	Exon 2 of 3	ENST00000439435.3	NP_003859.1	O43320A0A7U3L5H2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
FGF16	ENST00000439435.3 link	c.275-3_275-2insAGGAATCCTGGAGTTTATC	splice_acceptor_variant, intron_variant	Intron 1 of 2	1	NM_003868.3	ENSP00000399324.2	O43320
ENSG00000295984	ENST00000734738.1 link	n.179+7051_179+7052insGATAAACTCCAGGATTCCT	intron_variant	Intron 1 of 1
ENSG00000295984	ENST00000734739.1 link	n.45+7051_45+7052insGATAAACTCCAGGATTCCT	intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

9.39e-7

AC:

AN:

1064937

Hom.:

Cov.:

AF XY:

0.00000298

AC XY:

AN XY:

335887

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25729

American (AMR)

AF:

0.00

AC:

AN:

34729

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19106

East Asian (EAS)

AF:

0.00

AC:

AN:

29973

South Asian (SAS)

AF:

0.00

AC:

AN:

52403

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40251

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4065

European-Non Finnish (NFE)

AF:

0.00000123

AC:

AN:

813656

Other (OTH)

AF:

0.00

AC:

AN:

45025

Age Distribution

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

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

Name

Calibrated prediction

Score

Prediction

PhyloP100

9.2

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over