1-27612931-G-A

Variant names:

• chr1-27612931-G-A
• rs143850913
• NM_005248.3:c.1573C>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_005248.3(FGR):​c.1573C>T​(p.Pro525Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000234 in 1,613,986 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 (no stars).

• Frequency:
  • Genomes: 𝑓 0.00065 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: FGR NM_005248.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 9.94

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06930527).
• BS2: High AC in GnomAd4 at 99 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGR	NM_005248.3	c.1573C>T	p.Pro525Ser	missense_variant	Exon 13 of 13	ENST00000374005.8	NP_005239.1
FGR	NM_001042729.2	c.1573C>T	p.Pro525Ser	missense_variant	Exon 13 of 13		NP_001036194.1
FGR	NM_001042747.2	c.1573C>T	p.Pro525Ser	missense_variant	Exon 13 of 13		NP_001036212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGR	ENST00000374005.8	c.1573C>T	p.Pro525Ser	missense_variant	Exon 13 of 13	1	NM_005248.3	ENSP00000363117.3
FGR	ENST00000374004.5	c.1573C>T	p.Pro525Ser	missense_variant	Exon 11 of 11	1		ENSP00000363116.1
FGR	ENST00000374003.7	c.1573C>T	p.Pro525Ser	missense_variant	Exon 13 of 13	2		ENSP00000363115.3
FGR	ENST00000399173.5	c.1573C>T	p.Pro525Ser	missense_variant	Exon 13 of 13	5		ENSP00000382126.1

Frequencies

GnomAD3 genomes AF: 0.000650 AC: 99 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000311 AC: 78 AN: 251026 Hom.: 0 AF XY: 0.000258 AC XY: 35 AN XY: 135686

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00162

Gnomad NFE exome AF: 0.0000969

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000191 AC: 279 AN: 1461666 Hom.: 0 Cov.: 31 AF XY: 0.000180 AC XY: 131 AN XY: 727122

Gnomad4 AFR exome AF: 0.00146

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00118

Gnomad4 NFE exome AF: 0.000123

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.000650 AC: 99 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.000577 AC XY: 43 AN XY: 74488

Gnomad4 AFR AF: 0.00173

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000218 Hom.: 0

Bravo AF: 0.000752

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000214 AC: 26

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:1

Nov 04, 2020

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.36	T;T;T;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	.;D;.;.
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.069	T;T;T;T
MetaSVM	Uncertain	-0.038	T
MutationAssessor	Benign	0.83	L;L;L;L
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.8	D;D;D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.014	D;D;D;D
Polyphen		0.99	D;D;D;D
Vest4		0.55
MVP		0.90
MPC		1.7
ClinPred		0.078	T
GERP RS		4.7
Varity_R		0.40
gMVP		0.48

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: rs143850913; hg19: chr1-27939442;