1-27614496-C-T

Variant names:

• chr1-27614496-C-T
• rs1200858737
• NM_005248.3:c.1183G>A

Variant summary

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

The NM_005248.3(FGR):​c.1183G>A​(p.Ala395Thr) 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 1,461,602 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A395V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FGR NM_005248.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.82

Genes affected

FGR (HGNC:3697): (FGR proto-oncogene, Src family tyrosine kinase) This gene is a member of the Src family of protein tyrosine kinases (PTKs). The encoded protein contains N-terminal sites for myristylation and palmitylation, a PTK domain, and SH2 and SH3 domains which are involved in mediating protein-protein interactions with phosphotyrosine-containing and proline-rich motifs, respectively. The protein localizes to plasma membrane ruffles, and functions as a negative regulator of cell migration and adhesion triggered by the beta-2 integrin signal transduction pathway. Infection with Epstein-Barr virus results in the overexpression of this gene. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Jul 2008]

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=0.24451736).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGR	NM_005248.3	c.1183G>A	p.Ala395Thr	missense_variant	Exon 11 of 13	ENST00000374005.8	NP_005239.1
FGR	NM_001042729.2	c.1183G>A	p.Ala395Thr	missense_variant	Exon 11 of 13		NP_001036194.1
FGR	NM_001042747.2	c.1183G>A	p.Ala395Thr	missense_variant	Exon 11 of 13		NP_001036212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGR	ENST00000374005.8	c.1183G>A	p.Ala395Thr	missense_variant	Exon 11 of 13	1	NM_005248.3	ENSP00000363117.3
FGR	ENST00000374004.5	c.1183G>A	p.Ala395Thr	missense_variant	Exon 9 of 11	1		ENSP00000363116.1
FGR	ENST00000374003.7	c.1183G>A	p.Ala395Thr	missense_variant	Exon 11 of 13	2		ENSP00000363115.3
FGR	ENST00000399173.5	c.1183G>A	p.Ala395Thr	missense_variant	Exon 11 of 13	5		ENSP00000382126.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461602 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727066

Gnomad4 AFR exome AF: 0.0000299

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

Mar 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1183G>A (p.A395T) alteration is located in exon 11 (coding exon 9) of the FGR gene. This alteration results from a G to A substitution at nucleotide position 1183, causing the alanine (A) at amino acid position 395 to be replaced by a threonine (T). 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	0.067
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;T;T;T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.74	.;T;.;.
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.24	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.48	N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.21	N;N;N;N
REVEL	Benign	0.038
Sift	Benign	0.049	D;D;D;D
Sift4G	Benign	0.26	T;T;T;T
Polyphen		0.0030	B;B;B;B
Vest4		0.35
MutPred		0.32		Gain of ubiquitination at K397 (P = 0.0882);Gain of ubiquitination at K397 (P = 0.0882);Gain of ubiquitination at K397 (P = 0.0882);Gain of ubiquitination at K397 (P = 0.0882);
MVP		0.58
MPC		0.79
ClinPred		0.21	T
GERP RS		3.1
Varity_R		0.043
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1200858737; hg19: chr1-27941007;