6-10409915-T-C

Variant names:

• chr6-10409915-T-C
• rs751678511
• NM_001372066.1:c.472A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001372066.1(TFAP2A):​c.472A>G​(p.Ile158Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000445 in 1,549,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I158M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: TFAP2A NM_001372066.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.91
• Publications: 0 publications found

Genes affected

TFAP2A (HGNC:11742): (transcription factor AP-2 alpha) The protein encoded by this gene is a transcription factor that binds the consensus sequence 5'-GCCNNNGGC-3'. The encoded protein functions as either a homodimer or as a heterodimer with similar family members. This protein activates the transcription of some genes while inhibiting the transcription of others. Defects in this gene are a cause of branchiooculofacial syndrome (BOFS). Three transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Dec 2009]

TFAP2A-AS1 (HGNC:40579): (TFAP2A antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05719915).
• BP6: Variant 6-10409915-T-C is Benign according to our data. Variant chr6-10409915-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3707910.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 65 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001372066.1. 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
	TFAP2A	NM_001372066.1	MANE Select	c.472A>G	p.Ile158Val	missense	Exon 2 of 7	NP_001358995.1	A0A6E1XE14
	TFAP2A	NM_001042425.3		c.454A>G	p.Ile152Val	missense	Exon 2 of 7	NP_001035890.1	P05549-6
	TFAP2A	NM_001032280.3		c.448A>G	p.Ile150Val	missense	Exon 2 of 7	NP_001027451.1	P05549-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFAP2A	ENST00000379613.10	TSL:1 MANE Select	c.472A>G	p.Ile158Val	missense	Exon 2 of 7	ENSP00000368933.5	A0A6E1XE14
	TFAP2A	ENST00000379608.9	TSL:1	c.448A>G	p.Ile150Val	missense	Exon 2 of 7	ENSP00000368928.3	P05549-5
	TFAP2A	ENST00000466073.5	TSL:1	c.466A>G	p.Ile156Val	missense	Exon 2 of 6	ENSP00000417495.1	C1K3N0

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000128 AC: 20 AN: 155928 AF XY: 0.0000847

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000402

Gnomad ASJ exome AF: 0.00176

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000334

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000465 AC: 65 AN: 1397494 Hom.: 0 Cov.: 32 AF XY: 0.0000465 AC XY: 32 AN XY: 688832

African (AFR) AF: 0.00 AC: 0 AN: 31610

American (AMR) AF: 0.00 AC: 0 AN: 35748

Ashkenazi Jewish (ASJ) AF: 0.00123 AC: 31 AN: 25156

East Asian (EAS) AF: 0.00 AC: 0 AN: 35696

South Asian (SAS) AF: 0.000101 AC: 8 AN: 79474

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48900

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5686

European-Non Finnish (NFE) AF: 0.0000186 AC: 20 AN: 1077342

Other (OTH) AF: 0.0000864 AC: 5 AN: 57882

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152088 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74286

African (AFR) AF: 0.00 AC: 0 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000120 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000756 AC: 8

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.055
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.90	L
PhyloP100		4.9
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.22
Sift	Benign	0.29	T
Sift4G	Benign	0.59	T
Polyphen		0.65	P
Vest4		0.43
MutPred		0.22		Gain of disorder (P = 0.1981)
MVP		0.64
ClinPred		0.12	T
GERP RS		5.1
PromoterAI		-0.086	Neutral
Varity_R		0.13
Mutation Taster		=90/10	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: rs751678511; hg19: chr6-10410148;