rs1483153935

Variant names:

• chr7-38417857-T-C
• rs1483153935
• NM_001635.4:c.1366A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001635.4(AMPH):​c.1366A>G​(p.Thr456Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,613,980 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: AMPH NM_001635.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.617
• Publications: 0 publications found

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

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.048295736).

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.1366A>G	p.Thr456Ala	missense	Exon 17 of 21	NP_001626.1	P49418-1
	AMPH	NM_139316.3		c.1272+4564A>G		intron	N/A	NP_647477.1	P49418-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMPH	ENST00000356264.7	TSL:1 MANE Select	c.1366A>G	p.Thr456Ala	missense	Exon 17 of 21	ENSP00000348602.2	P49418-1
	AMPH	ENST00000325590.9	TSL:1	c.1272+4564A>G		intron	N/A	ENSP00000317441.5	P49418-2
	AMPH	ENST00000441628.5	TSL:1	c.1044+4564A>G		intron	N/A	ENSP00000415085.1	H0Y7T8

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 251056 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000294 AC: 43 AN: 1461792 Hom.: 0 Cov.: 30 AF XY: 0.0000234 AC XY: 17 AN XY: 727188

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000369 AC: 41 AN: 1111956

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74352

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000847 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	3.4
DANN	Benign	0.92
DEOGEN2	Benign	0.059	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.62
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.079
Sift	Benign	0.34	T
Sift4G	Benign	0.78	T
Polyphen		0.0	B
Vest4		0.19
MutPred		0.15		Loss of glycosylation at T456 (P = 0.0654)
MVP		0.72
MPC		0.18
ClinPred		0.045	T
GERP RS		2.7
Varity_R		0.073
gMVP		0.11
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs1483153935; hg19: chr7-38457457;