chr6-41771175-C-G

Variant names:

• chr6-41771175-C-G
• rs1772280961
• NM_006653.5:c.923G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006653.5(FRS3):​c.923G>C​(p.Gly308Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FRS3 NM_006653.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.15

Genes affected

FRS3 (HGNC:16970): (fibroblast growth factor receptor substrate 3) This gene encodes a substrate for the fibroblast growth factor receptor. The encoded protein is found in the peripheral plasma membrane and links fibroblast growth factor receptor stimulation to activators of Ras. The encoded protein down-regulates extracellular regulated kinase 2 through direct binding. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07119036).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRS3	NM_006653.5	c.923G>C	p.Gly308Ala	missense_variant	Exon 7 of 7	ENST00000373018.7	NP_006644.1
FRS3	XM_011514254.2	c.923G>C	p.Gly308Ala	missense_variant	Exon 7 of 7		XP_011512556.1
FRS3	XM_047418097.1	c.923G>C	p.Gly308Ala	missense_variant	Exon 8 of 8		XP_047274053.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRS3	ENST00000373018.7	c.923G>C	p.Gly308Ala	missense_variant	Exon 7 of 7	3	NM_006653.5	ENSP00000362109.3
FRS3	ENST00000259748.6	c.923G>C	p.Gly308Ala	missense_variant	Exon 6 of 6	1		ENSP00000259748.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1402246 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 689582

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 26, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.923G>C (p.G308A) alteration is located in exon 7 (coding exon 5) of the FRS3 gene. This alteration results from a G to C substitution at nucleotide position 923, causing the glycine (G) at amino acid position 308 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	17
DANN	Benign	0.76
DEOGEN2	Benign	0.18	T;T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.018
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.69	T;.
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.071	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.96	N;N
REVEL	Benign	0.015
Sift	Benign	0.11	T;T
Sift4G	Uncertain	0.059	T;T
Polyphen		0.024	B;B
Vest4		0.089
MutPred		0.21		Loss of catalytic residue at P304 (P = 0.0722);Loss of catalytic residue at P304 (P = 0.0722);
MVP		0.24
MPC		0.25
ClinPred		0.068	T
GERP RS		4.6
Varity_R		0.077
gMVP		0.13

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

Other links and lift over

dbSNP: rs1772280961; hg19: chr6-41738913;