chr6-41771092-C-T

Variant names:

• chr6-41771092-C-T
• rs748438007
• NM_006653.5:c.1006G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_006653.5(FRS3):​c.1006G>A​(p.Ala336Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000314 in 1,593,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: FRS3 NM_006653.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.657
• Publications: 1 publications found

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

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.046895534).
• BS2: High AC in GnomAdExome4 at 46 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006653.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRS3	NM_006653.5	MANE Select	c.1006G>A	p.Ala336Thr	missense	Exon 7 of 7	NP_006644.1	O43559

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRS3	ENST00000373018.7	TSL:3 MANE Select	c.1006G>A	p.Ala336Thr	missense	Exon 7 of 7	ENSP00000362109.3	O43559
	FRS3	ENST00000259748.6	TSL:1	c.1006G>A	p.Ala336Thr	missense	Exon 6 of 6	ENSP00000259748.2	O43559
	FRS3	ENST00000930712.1		c.1006G>A	p.Ala336Thr	missense	Exon 7 of 7	ENSP00000600771.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152078 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000339 AC: 8 AN: 235906 AF XY: 0.0000236

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000599

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000562

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000319 AC: 46 AN: 1441848 Hom.: 0 Cov.: 33 AF XY: 0.0000308 AC XY: 22 AN XY: 714272

African (AFR) AF: 0.00 AC: 0 AN: 33098

American (AMR) AF: 0.0000459 AC: 2 AN: 43578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24794

East Asian (EAS) AF: 0.00 AC: 0 AN: 39394

South Asian (SAS) AF: 0.00 AC: 0 AN: 83376

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52520

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5670

European-Non Finnish (NFE) AF: 0.0000400 AC: 44 AN: 1099990

Other (OTH) AF: 0.00 AC: 0 AN: 59428

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152078 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74270

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41418

American (AMR) AF: 0.000131 AC: 2 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000478 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	11
DANN	Benign	0.97
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.66
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.95	N
REVEL	Benign	0.087
Sift	Uncertain	0.023	D
Sift4G	Benign	0.50	T
Polyphen		0.10	B
Vest4		0.047
MVP		0.19
MPC		0.22
ClinPred		0.035	T
GERP RS		2.8
Varity_R		0.037
gMVP		0.19
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs748438007; hg19: chr6-41738830;