4-7763774-G-C

Variant names:

• chr4-7763774-G-C
• rs114329356
• NM_001134647.2:c.2436C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001134647.2(AFAP1):​c.2436C>G​(p.Asn812Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000214 in 1,399,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N812N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: AFAP1 NM_001134647.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.336
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13664374).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134647.2. 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
	AFAP1	NM_001134647.2	MANE Select	c.2436C>G	p.Asn812Lys	missense	Exon 18 of 18	NP_001128119.1	Q8N556-2
	AFAP1	NM_001371090.1		c.2184C>G	p.Asn728Lys	missense	Exon 16 of 16	NP_001358019.1	Q8N556-1
	AFAP1	NM_001371091.1		c.2184C>G	p.Asn728Lys	missense	Exon 18 of 18	NP_001358020.1	Q8N556-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFAP1	ENST00000420658.6	TSL:2 MANE Select	c.2436C>G	p.Asn812Lys	missense	Exon 18 of 18	ENSP00000410689.1	Q8N556-2
	AFAP1	ENST00000360265.9	TSL:1	c.2184C>G	p.Asn728Lys	missense	Exon 16 of 16	ENSP00000353402.4	Q8N556-1
	AFAP1-AS1	ENST00000608442.2	TSL:1	n.84-8430G>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000214 AC: 3 AN: 1399398 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 690228

African (AFR) AF: 0.00 AC: 0 AN: 31594

American (AMR) AF: 0.00 AC: 0 AN: 35726

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25180

East Asian (EAS) AF: 0.00 AC: 0 AN: 35744

South Asian (SAS) AF: 0.00 AC: 0 AN: 79228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49306

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1078924

Other (OTH) AF: 0.00 AC: 0 AN: 58000

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	2.8
DANN	Benign	0.80
DEOGEN2	Benign	0.0086	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.52	N
PhyloP100		-0.34
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	1.3	N
REVEL	Benign	0.075
Sift	Benign	0.50	T
Sift4G	Benign	0.82	T
Polyphen		0.86	P
Vest4		0.53
MutPred		0.19		Gain of methylation at N728 (P = 0.0202)
MVP		0.040
MPC		0.46
ClinPred		0.28	T
GERP RS		-1.6
Varity_R		0.076
gMVP		0.087
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs114329356; hg19: chr4-7765501;