chr7-38391990-C-G

Variant names:

• chr7-38391990-C-G
• rs1257054366
• NM_001635.4:c.1636G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001635.4(AMPH):​c.1636G>C​(p.Glu546Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000412 in 1,455,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: AMPH NM_001635.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.24
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15213522).

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.1636G>C	p.Glu546Gln	missense	Exon 19 of 21	NP_001626.1	P49418-1
	AMPH	NM_139316.3		c.1510G>C	p.Glu504Gln	missense	Exon 18 of 20	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.1636G>C	p.Glu546Gln	missense	Exon 19 of 21	ENSP00000348602.2	P49418-1
	AMPH	ENST00000325590.9	TSL:1	c.1510G>C	p.Glu504Gln	missense	Exon 18 of 20	ENSP00000317441.5	P49418-2
	AMPH	ENST00000441628.5	TSL:1	c.1282G>C	p.Glu428Gln	missense	Exon 10 of 12	ENSP00000415085.1	H0Y7T8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000412 AC: 6 AN: 1455430 Hom.: 0 Cov.: 34 AF XY: 0.00000276 AC XY: 2 AN XY: 724286

African (AFR) AF: 0.00 AC: 0 AN: 33438

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48272

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4766

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111954

Other (OTH) AF: 0.00 AC: 0 AN: 60248

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

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	0.27
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.020
Eigen_PC	Benign	0.044
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.7	L
PhyloP100		3.2
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.093
Sift	Benign	0.076	T
Sift4G	Benign	0.099	T
Polyphen		0.14	B
Vest4		0.14
MutPred		0.10		Loss of phosphorylation at S549 (P = 0.0956)
MVP		0.76
MPC		0.22
ClinPred		0.90	D
GERP RS		3.9
Varity_R		0.27
gMVP		0.35
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1257054366; hg19: chr7-38431591;