16-56369218-C-G

Variant names:

• chr16-56369218-C-G
• rs750744117
• NM_001144.6:c.1490G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001144.6(AMFR):​c.1490G>C​(p.Arg497Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R497Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: AMFR NM_001144.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.89
• Publications: 2 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.857

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.1490G>C	p.Arg497Pro	missense	Exon 11 of 14	NP_001135.3
	AMFR	NM_001323512.2		c.1586G>C	p.Arg529Pro	missense	Exon 12 of 15	NP_001310441.1
	AMFR	NM_001323511.2		c.1205G>C	p.Arg402Pro	missense	Exon 11 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.1490G>C	p.Arg497Pro	missense	Exon 11 of 14	ENSP00000290649.5	Q9UKV5
	AMFR	ENST00000861442.1		c.1490G>C	p.Arg497Pro	missense	Exon 11 of 14	ENSP00000531501.1
	AMFR	ENST00000861443.1		c.1460G>C	p.Arg487Pro	missense	Exon 11 of 14	ENSP00000531502.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.9
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.70		Gain of helix (P = 0.062)
MVP		0.69
MPC		1.7
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.91
gMVP		0.90

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: rs750744117; hg19: chr16-56403130;