7-38436278-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001635.4(AMPH):c.1128G>C(p.Met376Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.005 in 1,613,478 control chromosomes in the GnomAD database, including 340 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.027 (184 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (156 hom.)
• Consequence: AMPH NM_001635.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.33

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001930207).
• BP6: Variant 7-38436278-C-G is Benign according to our data. Variant chr7-38436278-C-G is described in ClinVar as [Benign]. Clinvar id is 776216.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.09 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AMPH	NM_001635.4	c.1128G>C	p.Met376Ile	missense_variant	12/21	ENST00000356264.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AMPH	ENST00000356264.7	c.1128G>C	p.Met376Ile	missense_variant	12/21	1	NM_001635.4	P3
AMPH	ENST00000325590.9	c.1128G>C	p.Met376Ile	missense_variant	12/20	1		A2
AMPH	ENST00000441628.5	c.381G>C	p.Met127Ile	missense_variant	3/12	1

Frequencies

GnomAD3 genomes AF: 0.0274 AC: 4176 AN: 152148 Hom.: 182 Cov.: 32

Gnomad AFR AF: 0.0925

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0171

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.0253

GnomAD3 exomes AF: 0.00714 AC: 1796 AN: 251394 Hom.: 77 AF XY: 0.00545 AC XY: 741 AN XY: 135878

Gnomad AFR exome AF: 0.0937

Gnomad AMR exome AF: 0.00628

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000237

Gnomad OTH exome AF: 0.00456

GnomAD4 exome AF: 0.00266 AC: 3890 AN: 1461212 Hom.: 156 Cov.: 30 AF XY: 0.00234 AC XY: 1703 AN XY: 726966

Gnomad4 AFR exome AF: 0.0890

Gnomad4 AMR exome AF: 0.00731

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000109

Gnomad4 OTH exome AF: 0.00686

GnomAD4 genome AF: 0.0275 AC: 4181 AN: 152266 Hom.: 184 Cov.: 32 AF XY: 0.0273 AC XY: 2033 AN XY: 74448

Gnomad4 AFR AF: 0.0924

Gnomad4 AMR AF: 0.0170

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.0251

Alfa AF: 0.00163 Hom.: 10

Bravo AF: 0.0326

ESP6500AA AF: 0.0826 AC: 364

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00841 AC: 1021

Asia WGS AF: 0.00635 AC: 23 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	23
Dann	Benign	0.83
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D;D
MetaRNN	Benign	0.0019	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.67	N;N
MutationTaster	Benign	0.96	D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.12
Sift	Benign	0.41	T;T
Sift4G	Benign	0.23	T;T
Polyphen		0.010	B;B
Vest4		0.48
MutPred		0.092		Loss of disorder (P = 0.049);Loss of disorder (P = 0.049);
MVP		0.74
MPC		0.21
ClinPred		0.0064	T
GERP RS		5.5
Varity_R		0.22
gMVP		0.087

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs17171345; hg19: chr7-38475878;