16-56389364-C-G

Variant names:

• chr16-56389364-C-G
• rs745966114
• NM_001144.6:c.1097G>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.1097G>C​(p.Arg366Pro) 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. R366H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AMFR NM_001144.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.88
• 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, 0.881

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.1097G>C	p.Arg366Pro	missense	Exon 9 of 14	NP_001135.3
	AMFR	NM_001323512.2		c.1097G>C	p.Arg366Pro	missense	Exon 9 of 15	NP_001310441.1
	AMFR	NM_001323511.2		c.812G>C	p.Arg271Pro	missense	Exon 9 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.1097G>C	p.Arg366Pro	missense	Exon 9 of 14	ENSP00000290649.5	Q9UKV5
	AMFR	ENST00000861442.1		c.1097G>C	p.Arg366Pro	missense	Exon 9 of 14	ENSP00000531501.1
	AMFR	ENST00000861443.1		c.1097G>C	p.Arg366Pro	missense	Exon 9 of 14	ENSP00000531502.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.094	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Pathogenic	3.6	H
PhyloP100		7.9
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.033	D
Polyphen		0.97	D
Vest4		0.93
MutPred		0.79		Loss of catalytic residue at R366 (P = 0.0432)
MVP		0.67
MPC		1.6
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.79
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs745966114; hg19: chr16-56423276; COSMIC: COSV51921033; COSMIC: COSV51921033;