10-114314042-T-G

Variant names:

• chr10-114314042-T-G
• rs621375
• NM_001001936.3:c.621A>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001001936.3(AFAP1L2):​c.621A>C​(p.Lys207Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AFAP1L2 NM_001001936.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.472
• Publications: 15 publications found

Genes affected

AFAP1L2 (HGNC:25901): (actin filament associated protein 1 like 2) Enables SH2 domain binding activity; SH3 domain binding activity; and protein tyrosine kinase activator activity. Involved in several processes, including positive regulation of epidermal growth factor receptor signaling pathway; regulation of gene expression; and regulation of mitotic cell cycle. Located in cytosol and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000299554 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001001936.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFAP1L2	NM_001001936.3	MANE Select	c.621A>C	p.Lys207Asn	missense	Exon 7 of 19	NP_001001936.1	Q8N4X5-1
	AFAP1L2	NM_001287824.2		c.780A>C	p.Lys260Asn	missense	Exon 8 of 20	NP_001274753.1
	AFAP1L2	NM_001351065.2		c.705A>C	p.Lys235Asn	missense	Exon 8 of 20	NP_001337994.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFAP1L2	ENST00000304129.9	TSL:1 MANE Select	c.621A>C	p.Lys207Asn	missense	Exon 7 of 19	ENSP00000303042.4	Q8N4X5-1
	AFAP1L2	ENST00000369271.7	TSL:1	c.621A>C	p.Lys207Asn	missense	Exon 7 of 19	ENSP00000358276.3	Q8N4X5-2
	AFAP1L2	ENST00000941481.1		c.864A>C	p.Lys288Asn	missense	Exon 9 of 21	ENSP00000611540.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250406 AF XY: 0.00

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D
Eigen	Uncertain	0.33
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		0.47
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.81
MVP		0.88
MPC		0.70
ClinPred		0.99	D
GERP RS		1.2
Varity_R		0.80
gMVP		0.81
Mutation Taster		=72/28	polymorphism

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

Other links and lift over

dbSNP: rs621375; hg19: chr10-116073801;