Genetic Variant AMPH:p.Thr586Met (chr7-38391869-G-A) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001635.4(AMPH):c.1757C>T(p.Thr586Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00283 in 1,612,822 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0029 ( 5 hom. )

Consequence

AMPH
NM_001635.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.623

Publications

4 publications found

Variant links:

Genes affected

AMPH (HGNC:471): (amphiphysin) This gene encodes a protein associated with the cytoplasmic surface of synaptic vesicles. A subset of patients with stiff-man syndrome who were also affected by breast cancer are positive for autoantibodies against this protein. Alternate splicing of this gene results in two transcript variants encoding different isoforms. Additional splice variants have been described, but their full length sequences have not been determined. A pseudogene of this gene is found on chromosome 11.[provided by RefSeq, Nov 2010]

AMPH links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006348312).

BP6

Variant 7-38391869-G-A is Benign according to our data. Variant chr7-38391869-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 711336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 5 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001635.4. 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
	AMPH	NM_001635.4	MANE Select	c.1757C>T	p.Thr586Met	missense	Exon 19 of 21	NP_001626.1	P49418-1
	AMPH	NM_139316.3		c.1631C>T	p.Thr544Met	missense	Exon 18 of 20	NP_647477.1	P49418-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AMPH	ENST00000356264.7	TSL:1 MANE Select	c.1757C>T	p.Thr586Met	missense	Exon 19 of 21	ENSP00000348602.2	P49418-1
AMPH	ENST00000325590.9	TSL:1	c.1631C>T	p.Thr544Met	missense	Exon 18 of 20	ENSP00000317441.5	P49418-2
AMPH	ENST00000441628.5	TSL:1	c.1403C>T	p.Thr468Met	missense	Exon 10 of 12	ENSP00000415085.1	H0Y7T8

Frequencies

GnomAD3 genomes

AF:

0.00178

AC:

271

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000772

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00605

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00269

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.00198

AC:

495

AN:

249932

AF XY:

0.00200

show subpopulations

Gnomad AFR exome

AF:

0.000555

Gnomad AMR exome

AF:

0.00175

Gnomad ASJ exome

AF:

0.00301

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000187

Gnomad NFE exome

AF:

0.00311

Gnomad OTH exome

AF:

0.00214

GnomAD4 exome

AF:

0.00294

AC:

4289

AN:

1460580

Hom.:

Cov.:

AF XY:

0.00286

AC XY:

2077

AN XY:

726596

show subpopulations

African (AFR)

AF:

0.000688

AC:

AN:

33426

American (AMR)

AF:

0.00209

AC:

AN:

44558

Ashkenazi Jewish (ASJ)

AF:

0.00364

AC:

AN:

26074

East Asian (EAS)

AF:

0.000327

AC:

AN:

39698

South Asian (SAS)

AF:

0.000870

AC:

AN:

86174

European-Finnish (FIN)

AF:

0.000245

AC:

AN:

53156

Middle Eastern (MID)

AF:

0.000726

AC:

AN:

5506

European-Non Finnish (NFE)

AF:

0.00344

AC:

3828

AN:

1111690

Other (OTH)

AF:

0.00240

AC:

145

AN:

60298

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

257

513

770

1026

1283

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

304

456

608

760

<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:

0.00178

AC:

271

AN:

152242

Hom.:

Cov.:

AF XY:

0.00165

AC XY:

123

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.000770

AC:

AN:

41548

American (AMR)

AF:

0.00163

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00605

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.00125

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00269

AC:

183

AN:

68016

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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:

0.00251

Hom.:

Bravo

AF:

0.00182

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00314

AC:

ExAC

AF:

0.00187

AC:

227

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00387

EpiControl

AF:

0.00379

ClinVar

ClinVar submissions

Significance:Likely 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

0.074

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.15

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.040

LIST_S2

Benign

0.46

M_CAP

Benign

0.027

MetaRNN

Benign

0.0063

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.49

PhyloP100

-0.62

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.3

REVEL

Benign

0.031

Sift

Benign

0.13

Sift4G

Benign

0.095

Polyphen

0.0070

Vest4

0.077

MVP

0.66

MPC

0.20

ClinPred

0.0048

GERP RS

0.27

Varity_R

0.015

gMVP

0.21

Mutation Taster

=97/3

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