Genetic Variant SH3RF1:p.Ala634Val (chr4-169116507-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020870.4(SH3RF1):c.1901C>T(p.Ala634Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00181 in 1,613,460 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0089 ( 16 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 15 hom. )

Consequence

SH3RF1
NM_020870.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.01

Publications

3 publications found

Variant links:

Genes affected

SH3RF1 (HGNC:17650): (SH3 domain containing ring finger 1) This gene encodes a protein containing an N-terminus RING-finger, four SH3 domains, and a region implicated in binding of the Rho GTPase Rac. Via the RING-finger, the encoded protein has been shown to function as an ubiquitin-protein ligase involved in protein sorting at the trans-Golgi network. The encoded protein may also act as a scaffold for the c-Jun N-terminal kinase signaling pathway, facilitating the formation of a functional signaling module. [provided by RefSeq, Jul 2008]

SH3RF1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002649963).

BP6

Variant 4-169116507-G-A is Benign according to our data. Variant chr4-169116507-G-A is described in ClinVar as Benign. ClinVar VariationId is 708813.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00894 (1362/152328) while in subpopulation AFR AF = 0.0306 (1271/41574). AF 95% confidence interval is 0.0292. There are 16 homozygotes in GnomAd4. There are 653 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 16 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020870.4. 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
	SH3RF1	NM_020870.4	MANE Select	c.1901C>T	p.Ala634Val	missense	Exon 10 of 12	NP_065921.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SH3RF1	ENST00000284637.14	TSL:1 MANE Select	c.1901C>T	p.Ala634Val	missense	Exon 10 of 12	ENSP00000284637.9	Q7Z6J0-1
SH3RF1	ENST00000508685.1	TSL:1	n.1782C>T		non_coding_transcript_exon	Exon 9 of 9
SH3RF1	ENST00000511421.5	TSL:1	n.*508C>T		non_coding_transcript_exon	Exon 8 of 8	ENSP00000426418.1	H0YA90

Frequencies

GnomAD3 genomes

AF:

0.00886

AC:

1348

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0303

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00379

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.00573

GnomAD2 exomes

AF:

0.00228

AC:

566

AN:

248724

AF XY:

0.00175

show subpopulations

Gnomad AFR exome

AF:

0.0293

Gnomad AMR exome

AF:

0.00169

Gnomad ASJ exome

AF:

0.0000996

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000215

Gnomad OTH exome

AF:

0.000983

GnomAD4 exome

AF:

0.00107

AC:

1557

AN:

1461132

Hom.:

Cov.:

AF XY:

0.000956

AC XY:

695

AN XY:

726812

show subpopulations

African (AFR)

AF:

0.0323

AC:

1083

AN:

33480

American (AMR)

AF:

0.00186

AC:

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.000128

AC:

AN:

86036

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53260

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000191

AC:

212

AN:

1111730

Other (OTH)

AF:

0.00262

AC:

158

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

186

280

373

466

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<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

AF:

0.00894

AC:

1362

AN:

152328

Hom.:

Cov.:

AF XY:

0.00877

AC XY:

653

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.0306

AC:

1271

AN:

41574

American (AMR)

AF:

0.00379

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000294

AC:

AN:

68026

Other (OTH)

AF:

0.00567

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

134

202

269

336

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00310

Hom.:

Bravo

AF:

0.00966

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0291

AC:

128

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00264

AC:

320

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000416

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.81

CADD

Benign

8.2

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.017

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.62

MetaRNN

Benign

0.0026

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.55

PhyloP100

1.0

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.41

REVEL

Benign

0.056

Sift

Benign

0.51

Sift4G

Benign

0.40

Polyphen

0.0010

Vest4

0.062

MVP

0.092

MPC

0.33

ClinPred

0.0029

GERP RS

-1.1

Varity_R

0.012

gMVP

0.098

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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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