Genetic Variant EFS:p.Arg343Pro (chr14-23359450-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_005864.4(EFS):c.1028G>C(p.Arg343Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R343H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 30)

Exomes 𝑓: 0.023 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

EFS
NM_005864.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0130

Publications

0 publications found

Variant links:

Genes affected

EFS (HGNC:16898): (embryonal Fyn-associated substrate) The protein encoded by this gene is a member of the CAS (CRK-associated substrate) family of adaptor proteins which typically serve as scaffolds for the assembly of larger signaling complexes. These complexes form at the cell surface where integrin binding leads to the subsequent phosphorylation of a CAS protein. Additional binding of SRC family kinases leads to CAS hyperphosphorylation and the creation of binding sites for CRK and other proteins that cause actin cytoskeleton reorganization. This gene plays a role in integrin-mediated cell attachment, spreading, and migration and also plays a role in both normal and malignant cellular transformation. This broadly expressed gene has been shown to play a role in neurite outgrowth and its expression in the thymus and lymphocytes is important for T cell maturation and the development of immunological self-tolerance. Alternative splicing of this gene results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2020]

EFS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15779388).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005864.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EFS	NM_005864.4	MANE Select	c.1028G>C	p.Arg343Pro	missense	Exon 4 of 6	NP_005855.1	O43281-1
EFS	NM_032459.3		c.749G>C	p.Arg250Pro	missense	Exon 3 of 5	NP_115835.1	O43281-2
EFS	NM_001385607.1		c.749G>C	p.Arg250Pro	missense	Exon 3 of 4	NP_001372536.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EFS	ENST00000216733.8	TSL:1 MANE Select	c.1028G>C	p.Arg343Pro	missense	Exon 4 of 6	ENSP00000216733.3	O43281-1
EFS	ENST00000351354.3	TSL:1	c.749G>C	p.Arg250Pro	missense	Exon 3 of 5	ENSP00000340607.3	O43281-2
EFS	ENST00000923553.1		c.1028G>C	p.Arg343Pro	missense	Exon 4 of 5	ENSP00000593612.1

Frequencies

GnomAD3 genomes

AF:

0.0000717

AC:

AN:

111554

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000647

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000838

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000338

Gnomad FIN

AF:

0.000155

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000589

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000481

AC:

AN:

187276

AF XY:

0.0000287

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000504

Gnomad ASJ exome

AF:

0.000297

Gnomad EAS exome

AF:

0.0000826

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000338

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0232

AC:

8997

AN:

388022

Hom.:

Cov.:

AF XY:

0.0204

AC XY:

4267

AN XY:

209554

show subpopulations

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

African (AFR)

AF:

0.0177

AC:

178

AN:

10042

American (AMR)

AF:

0.00117

AC:

AN:

20542

Ashkenazi Jewish (ASJ)

AF:

0.00756

AC:

AN:

8196

East Asian (EAS)

AF:

0.00474

AC:

AN:

8222

South Asian (SAS)

AF:

0.00494

AC:

223

AN:

45130

European-Finnish (FIN)

AF:

0.000728

AC:

AN:

24734

Middle Eastern (MID)

AF:

0.00845

AC:

AN:

2484

European-Non Finnish (NFE)

AF:

0.0320

AC:

8118

AN:

253842

Other (OTH)

AF:

0.0212

AC:

314

AN:

14830

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.256

Heterozygous variant carriers

1081

2162

3243

4324

5405

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

416

832

1248

1664

2080

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000717

AC:

AN:

111614

Hom.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

54992

show subpopulations

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

African (AFR)

AF:

0.0000646

AC:

AN:

30954

American (AMR)

AF:

0.0000836

AC:

AN:

11956

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2788

East Asian (EAS)

AF:

0.00

AC:

AN:

3306

South Asian (SAS)

AF:

0.000338

AC:

AN:

2956

European-Finnish (FIN)

AF:

0.000155

AC:

AN:

6456

Middle Eastern (MID)

AF:

0.00

AC:

AN:

188

European-Non Finnish (NFE)

AF:

0.0000589

AC:

AN:

50906

Other (OTH)

AF:

0.00

AC:

AN:

1534

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.231

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.075

Eigen

Benign

0.046

Eigen_PC

Benign

0.066

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.75

M_CAP

Benign

0.029

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.2

PhyloP100

-0.013

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.93

REVEL

Benign

0.16

Sift

Benign

0.20

Sift4G

Benign

0.35

Polyphen

0.97

Vest4

0.39

MutPred

0.30

Gain of glycosylation at R343 (P = 0.0054)

MVP

0.75

MPC

0.44

ClinPred

0.20

GERP RS

3.8

Varity_R

0.24

gMVP

0.56

Mutation Taster

=65/35

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over