16-56367527-G-A

Variant names:

• chr16-56367527-G-A
• rs202074356
• NM_001144.6:c.1516C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001144.6(AMFR):​c.1516C>T​(p.Arg506Trp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000874 in 1,612,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000082 (0 hom.)
• Consequence: AMFR NM_001144.6 missense, splice_region
• Scores: Splicing: ADA: 0.9920
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.74

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMFR	NM_001144.6	c.1516C>T	p.Arg506Trp	missense_variant, splice_region_variant	Exon 12 of 14	ENST00000290649.10	NP_001135.3
AMFR	NM_001323512.2	c.1612C>T	p.Arg538Trp	missense_variant, splice_region_variant	Exon 13 of 15		NP_001310441.1
AMFR	NM_001323511.2	c.1231C>T	p.Arg411Trp	missense_variant, splice_region_variant	Exon 12 of 14		NP_001310440.1
AMFR	XM_005255890.5	c.1231C>T	p.Arg411Trp	missense_variant, splice_region_variant	Exon 12 of 14		XP_005255947.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMFR	ENST00000290649.10	c.1516C>T	p.Arg506Trp	missense_variant, splice_region_variant	Exon 12 of 14	1	NM_001144.6	ENSP00000290649.5

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152080 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000877 AC: 22 AN: 250858 Hom.: 0 AF XY: 0.0000811 AC XY: 11 AN XY: 135646

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000331

Gnomad NFE exome AF: 0.0000880

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000821 AC: 120 AN: 1460770 Hom.: 0 Cov.: 31 AF XY: 0.0000798 AC XY: 58 AN XY: 726740

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000322

Gnomad4 NFE exome AF: 0.0000828

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152080 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74262

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000472

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000145 Hom.: 0

Bravo AF: 0.000110

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 17, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1516C>T (p.R506W) alteration is located in exon 12 (coding exon 12) of the AMFR gene. This alteration results from a C to T substitution at nucleotide position 1516, causing the arginine (R) at amino acid position 506 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.39	T;T;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;.;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.7	D;.;D
REVEL	Benign	0.19
Sift	Uncertain	0.0080	D;.;D
Sift4G	Uncertain	0.021	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.56
MVP		0.53
MPC		1.1
ClinPred		0.37	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.85
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

Publications

LitVar

Other links and lift over

dbSNP: rs202074356; hg19: chr16-56401439;