6-41770670-G-C

Variant names:

• chr6-41770670-G-C
• rs772489038
• NM_006653.5:c.1428C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006653.5(FRS3):​c.1428C>G​(p.Asp476Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FRS3 NM_006653.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.38

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31583035).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRS3	NM_006653.5	c.1428C>G	p.Asp476Glu	missense_variant	Exon 7 of 7	ENST00000373018.7	NP_006644.1
FRS3	XM_011514254.2	c.1428C>G	p.Asp476Glu	missense_variant	Exon 7 of 7		XP_011512556.1
FRS3	XM_047418097.1	c.1428C>G	p.Asp476Glu	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.1428C>G	p.Asp476Glu	missense_variant	Exon 7 of 7	3	NM_006653.5	ENSP00000362109.3
FRS3	ENST00000259748.6	c.1428C>G	p.Asp476Glu	missense_variant	Exon 6 of 6	1		ENSP00000259748.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251048 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135792

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461854 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727222

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: 0.0000116

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

May 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1428C>G (p.D476E) alteration is located in exon 7 (coding exon 5) of the FRS3 gene. This alteration results from a C to G substitution at nucleotide position 1428, causing the aspartic acid (D) at amino acid position 476 to be replaced by a glutamic acid (E). 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	Uncertain	0.39
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	3.4
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T;T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.28	N
LIST_S2	Uncertain	0.89	D;.
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.1	M;M
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.26
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.011	D;D
Polyphen		1.0	D;D
Vest4		0.33
MutPred		0.25		Gain of solvent accessibility (P = 0.0306);Gain of solvent accessibility (P = 0.0306);
MVP		0.55
MPC		0.54
ClinPred		0.90	D
GERP RS		-4.3
Varity_R		0.38
gMVP		0.32

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: rs772489038; hg19: chr6-41738408;