chr5-44305012-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_004465.2(FGF10):ā€‹c.610A>Gā€‹(p.Met204Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000644 in 1,613,974 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.00012 ( 0 hom., cov: 33)
Exomes š‘“: 0.000059 ( 1 hom. )

Consequence

FGF10
NM_004465.2 missense

Scores

1
3
15

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 8.02
Variant links:
Genes affected
FGF10 (HGNC:3666): (fibroblast growth factor 10) The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities, and are involved in a variety of biological processes, including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. This protein exhibits mitogenic activity for keratinizing epidermal cells, but essentially no activity for fibroblasts, which is similar to the biological activity of FGF7. Studies of the mouse homolog of suggested that this gene is required for embryonic epidermal morphogenesis including brain development, lung morphogenesis, and initiation of lim bud formation. This gene is also implicated to be a primary factor in the process of wound healing. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.015585661).
BP6
Variant 5-44305012-T-C is Benign according to our data. Variant chr5-44305012-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 907811.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2}.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000118 (18/152334) while in subpopulation EAS AF= 0.00347 (18/5190). AF 95% confidence interval is 0.00224. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 18 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FGF10NM_004465.2 linkc.610A>G p.Met204Val missense_variant Exon 3 of 3 ENST00000264664.5 NP_004456.1 O15520A0A7U3JW18
FGF10XM_005248264.5 linkc.610A>G p.Met204Val missense_variant Exon 4 of 4 XP_005248321.1 O15520A0A7U3JW18

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FGF10ENST00000264664.5 linkc.610A>G p.Met204Val missense_variant Exon 3 of 3 1 NM_004465.2 ENSP00000264664.4 O15520

Frequencies

GnomAD3 genomes
AF:
0.000118
AC:
18
AN:
152216
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00346
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000155
AC:
39
AN:
251354
Hom.:
0
AF XY:
0.000162
AC XY:
22
AN XY:
135838
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00212
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000588
AC:
86
AN:
1461640
Hom.:
1
Cov.:
31
AF XY:
0.0000509
AC XY:
37
AN XY:
727124
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00214
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.000118
AC:
18
AN:
152334
Hom.:
0
Cov.:
33
AF XY:
0.000107
AC XY:
8
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00347
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.000102
ExAC
AF:
0.000165
AC:
20
Asia WGS
AF:
0.000578
AC:
2
AN:
3476

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Oct 24, 2022
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Reported in a patient with a disorder of sexual development who also harbored a variant in the SRY gene (Wang et al., 2018); This variant is associated with the following publications: (PMID: 29582157, 32140723) -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Congenital absence of salivary gland Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.24
T
BayesDel_noAF
Benign
-0.12
CADD
Benign
23
DANN
Benign
0.93
DEOGEN2
Uncertain
0.49
T
Eigen
Benign
0.052
Eigen_PC
Uncertain
0.26
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Benign
0.49
T
M_CAP
Benign
0.035
D
MetaRNN
Benign
0.016
T
MetaSVM
Benign
-0.29
T
MutationAssessor
Benign
1.1
L
PrimateAI
Uncertain
0.50
T
PROVEAN
Benign
-0.98
N
REVEL
Benign
0.26
Sift
Benign
0.34
T
Sift4G
Benign
0.78
T
Polyphen
0.0080
B
Vest4
0.37
MVP
0.82
MPC
1.3
ClinPred
0.13
T
GERP RS
5.9
Varity_R
0.56
gMVP
0.34

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs150695565; hg19: chr5-44305114; COSMIC: COSV52931917; API