16-56385954-T-A

Variant names:

• chr16-56385954-T-A
• rs761117811
• NM_001144.6:c.1345A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001144.6(AMFR):​c.1345A>T​(p.Ile449Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I449V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AMFR NM_001144.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.95
• Publications: 0 publications found

Genes affected

AMFR (HGNC:463): (autocrine motility factor receptor) This locus encodes a glycosylated transmembrane receptor. Its ligand, autocrine motility factor, is a tumor motility-stimulating protein secreted by tumor cells. The encoded receptor is also a member of the E3 ubiquitin ligase family of proteins. It catalyzes ubiquitination and endoplasmic reticulum-associated degradation of specific proteins. [provided by RefSeq, Feb 2012]

AMFR Gene-Disease associations (from GenCC):

• spastic paraplegia 89, autosomal recessive

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26657516).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001144.6. 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
	AMFR	NM_001144.6	MANE Select	c.1345A>T	p.Ile449Phe	missense	Exon 10 of 14	NP_001135.3
	AMFR	NM_001323512.2		c.1441A>T	p.Ile481Phe	missense	Exon 11 of 15	NP_001310441.1
	AMFR	NM_001323511.2		c.1060A>T	p.Ile354Phe	missense	Exon 10 of 14	NP_001310440.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMFR	ENST00000290649.10	TSL:1 MANE Select	c.1345A>T	p.Ile449Phe	missense	Exon 10 of 14	ENSP00000290649.5	Q9UKV5
	AMFR	ENST00000861442.1		c.1345A>T	p.Ile449Phe	missense	Exon 10 of 14	ENSP00000531501.1
	AMFR	ENST00000861443.1		c.1345A>T	p.Ile449Phe	missense	Exon 10 of 14	ENSP00000531502.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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	0.10
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	23
DANN	Benign	0.94
DEOGEN2	Benign	0.15	T
Eigen	Benign	0.082
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M
PhyloP100		4.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.12
Sift	Benign	0.39	T
Sift4G	Benign	0.74	T
Polyphen		0.29	B
Vest4		0.66
MutPred		0.31		Gain of catalytic residue at I449 (P = 0.0668)
MVP		0.48
MPC		0.81
ClinPred		0.78	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.13
gMVP		0.75

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: rs761117811; hg19: chr16-56419866;