Genetic Variant AFAP1L1:p.Ile142Val (chr5-149302514-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_152406.4(AFAP1L1):c.424A>G(p.Ile142Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000297 in 1,581,744 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 0.00016 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

AFAP1L1
NM_152406.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.52

Variant links:

Genes affected

AFAP1L1 (HGNC:26714): (actin filament associated protein 1 like 1) Predicted to enable SH3 domain binding activity. Predicted to be located in cell junction; cell projection; and podosome. Predicted to be active in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

AFAP1L1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFAP1L1	NM_152406.4 link	c.424A>G	p.Ile142Val	missense_variant	Exon 5 of 19	ENST00000296721.9	NP_689619.1	Q8TED9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AFAP1L1	ENST00000296721.9 link	c.424A>G	p.Ile142Val	missense_variant	Exon 5 of 19	1	NM_152406.4	ENSP00000296721.4		Q8TED9-1

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

151800

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000508

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000409

AC:

AN:

195578

Hom.:

AF XY:

0.0000192

AC XY:

AN XY:

104138

show subpopulations

Gnomad AFR exome

AF:

0.000664

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000161

AC:

AN:

1429944

Hom.:

Cov.:

AF XY:

0.00000848

AC XY:

AN XY:

707862

show subpopulations

Gnomad4 AFR exome

AF:

0.000574

Gnomad4 AMR exome

AF:

0.0000503

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000338

GnomAD4 genome

AF:

0.000158

AC:

AN:

151800

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74116

show subpopulations

Gnomad4 AFR

AF:

0.000508

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000195

Hom.:

Bravo

AF:

0.000257

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 10, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.424A>G (p.I142V) alteration is located in exon 5 (coding exon 5) of the AFAP1L1 gene. This alteration results from a A to G substitution at nucleotide position 424, causing the isoleucine (I) at amino acid position 142 to be replaced by a valine (V). 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

0.10

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.079

T;.

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.78

T;T

M_CAP

Benign

0.0088

MetaRNN

Benign

0.14

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

L;L

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.58

N;N

REVEL

Benign

0.15

Sift

Benign

0.23

T;T

Sift4G

Benign

0.097

T;T

Polyphen

0.98

D;B

Vest4

0.52

MVP

0.51

MPC

0.080

ClinPred

0.15

GERP RS

5.8

Varity_R

0.054

gMVP

0.26

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.49

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.49

Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over