5-149307612-T-C

Position:

• chr5-149307612-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The ENST00000296721.9(AFAP1L1):​c.746T>C​(p.Leu249Pro) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AFAP1L1 ENST00000296721.9 missense, splice_region
• Scores: Splicing: ADA: 0.9386
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.25

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AFAP1L1	NM_152406.4	c.746T>C	p.Leu249Pro	missense_variant, splice_region_variant	7/19	ENST00000296721.9	NP_689619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AFAP1L1	ENST00000296721.9	c.746T>C	p.Leu249Pro	missense_variant, splice_region_variant	7/19	1	NM_152406.4	ENSP00000296721	P1
AFAP1L1	ENST00000515000.1	c.746T>C	p.Leu249Pro	missense_variant, splice_region_variant	7/18	1		ENSP00000424427
AFAP1L1	ENST00000455574.6	n.844T>C		splice_region_variant, non_coding_transcript_exon_variant	7/9	1
AFAP1L1	ENST00000522492.1	n.870T>C		non_coding_transcript_exon_variant	8/8	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2024

The c.746T>C (p.L249P) alteration is located in exon 7 (coding exon 7) of the AFAP1L1 gene. This alteration results from a T to C substitution at nucleotide position 746, causing the leucine (L) at amino acid position 249 to be replaced by a proline (P). 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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		1.0	D;D
Vest4		0.88
MutPred		0.84		Gain of glycosylation at L249 (P = 0.0264);Gain of glycosylation at L249 (P = 0.0264);
MVP		0.45
MPC		0.62
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.93
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.94
dbscSNV1_RF	Pathogenic	0.82
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-148687175;