Genetic Variant NM_152406.4:c.248T>A (chr5-149301151-T-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_152406.4(AFAP1L1):c.248T>A(p.Leu83His) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 152,184 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Consequence

AFAP1L1
NM_152406.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.50

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152406.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AFAP1L1	NM_152406.4	MANE Select	c.248T>A	p.Leu83His	missense	Exon 4 of 19	NP_689619.1	Q8TED9-1
AFAP1L1	NM_001323062.2		c.248T>A	p.Leu83His	missense	Exon 4 of 18	NP_001309991.1
AFAP1L1	NM_001146337.3		c.248T>A	p.Leu83His	missense	Exon 4 of 18	NP_001139809.1	Q8TED9-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AFAP1L1	ENST00000296721.9	TSL:1 MANE Select	c.248T>A	p.Leu83His	missense	Exon 4 of 19	ENSP00000296721.4	Q8TED9-1
AFAP1L1	ENST00000515000.1	TSL:1	c.248T>A	p.Leu83His	missense	Exon 4 of 18	ENSP00000424427.1	Q8TED9-2
AFAP1L1	ENST00000455574.6	TSL:1	n.346T>A		non_coding_transcript_exon	Exon 4 of 9

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41446

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Uncertain

0.085

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.13

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.82

M_CAP

Benign

0.037

MetaRNN

Uncertain

0.60

MetaSVM

Benign

-0.64

MutationAssessor

Uncertain

2.5

PhyloP100

5.5

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.5

REVEL

Benign

0.24

Sift

Benign

0.17

Sift4G

Benign

0.087

Polyphen

1.0

Vest4

0.79

MutPred

0.29

Loss of stability (P = 0.0125)

MVP

0.65

MPC

0.55

ClinPred

0.90

GERP RS

5.0

Varity_R

0.22

gMVP

0.59

Mutation Taster

=63/37

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over