4-7772954-G-A

Variant names:

• chr4-7772954-G-A
• rs200872291
• NM_001134647.2:c.2119C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001134647.2(AFAP1):​c.2119C>T​(p.Arg707Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00056 in 1,613,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00058 (0 hom.)
• Consequence: AFAP1 NM_001134647.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.90

Genes affected

AFAP1 (HGNC:24017): (actin filament associated protein 1) The protein encoded by this gene is a Src binding partner. It may represent a potential modulator of actin filament integrity in response to cellular signals, and may function as an adaptor protein by linking Src family members and/or other signaling proteins to actin filaments. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

AFAP1-AS1 (HGNC:28141): (AFAP1 antisense RNA 1) This gene produces a long non-coding RNA that is overexpressed in tumor cells and may promote cancer cell metastasis. [provided by RefSeq, Dec 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11454508).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFAP1	NM_001134647.2	c.2119C>T	p.Arg707Trp	missense_variant	Exon 16 of 18	ENST00000420658.6	NP_001128119.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AFAP1	ENST00000420658.6	c.2119C>T	p.Arg707Trp	missense_variant	Exon 16 of 18	2	NM_001134647.2	ENSP00000410689.1

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152138 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000393 AC: 98 AN: 249470 Hom.: 0 AF XY: 0.000459 AC XY: 62 AN XY: 135030

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000668

Gnomad NFE exome AF: 0.000667

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.000579 AC: 846 AN: 1461106 Hom.: 0 Cov.: 31 AF XY: 0.000582 AC XY: 423 AN XY: 726926

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.000721

Gnomad4 NFE exome AF: 0.000692

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152256 Hom.: 0 Cov.: 33 AF XY: 0.000390 AC XY: 29 AN XY: 74440

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000588 Hom.: 0

Bravo AF: 0.000370

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000379 AC: 46

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2119C>T (p.R707W) alteration is located in exon 16 (coding exon 15) of the AFAP1 gene. This alteration results from a C to T substitution at nucleotide position 2119, causing the arginine (R) at amino acid position 707 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	0.22
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.33	T;T;.;.
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.68	D
LIST_S2	Pathogenic	0.99	.;D;D;.
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	2.0	M;M;.;.
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-5.9	D;D;D;D
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.42
MVP		0.37
MPC		0.42
ClinPred		0.20	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.64
gMVP		0.13

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

Publications

LitVar

Other links and lift over

dbSNP: rs200872291; hg19: chr4-7774681; COSMIC: COSV61795618;