7-38417881-C-T

Variant names:

• chr7-38417881-C-T
• rs373071104
• NM_001635.4:c.1342G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001635.4(AMPH):​c.1342G>A​(p.Val448Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000669 in 1,614,146 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 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000069 (0 hom.)
• Consequence: AMPH NM_001635.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.161
• 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05928853).

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.1342G>A	p.Val448Ile	missense	Exon 17 of 21	NP_001626.1	P49418-1
	AMPH	NM_139316.3		c.1272+4540G>A		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.1342G>A	p.Val448Ile	missense	Exon 17 of 21	ENSP00000348602.2	P49418-1
	AMPH	ENST00000325590.9	TSL:1	c.1272+4540G>A		intron	N/A	ENSP00000317441.5	P49418-2
	AMPH	ENST00000441628.5	TSL:1	c.1044+4540G>A		intron	N/A	ENSP00000415085.1	H0Y7T8

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.0000717 AC: 18 AN: 251100 AF XY: 0.0000811

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000705

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.0000691 AC: 101 AN: 1461826 Hom.: 0 Cov.: 30 AF XY: 0.0000701 AC XY: 51 AN XY: 727210

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53398

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5766

European-Non Finnish (NFE) AF: 0.0000585 AC: 65 AN: 1111984

Other (OTH) AF: 0.000232 AC: 14 AN: 60388

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74484

African (AFR) AF: 0.0000962 AC: 4 AN: 41576

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.0000666 Hom.: 0

Bravo AF: 0.0000302

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

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	0.081
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	9.3
DANN	Benign	0.79
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.16
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.072
Sift	Benign	0.21	T
Sift4G	Benign	0.21	T
Polyphen		0.029	B
Vest4		0.12
MVP		0.53
MPC		0.15
ClinPred		0.024	T
GERP RS		3.9
Varity_R		0.034
gMVP		0.055
Mutation Taster		=95/5	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: rs373071104; hg19: chr7-38457481;