6-50823875-A-G

Variant names:

• chr6-50823875-A-G
• rs72890675
• NM_003221.4:c.540+10A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6_Moderate

The NM_003221.4(TFAP2B):​c.540+10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000059 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: TFAP2B NM_003221.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0100
• Publications: 2 publications found

Genes affected

TFAP2B (HGNC:11743): (transcription factor AP-2 beta) This gene encodes a member of the AP-2 family of transcription factors. AP-2 proteins form homo- or hetero-dimers with other AP-2 family members and bind specific DNA sequences. They are thought to stimulate cell proliferation and suppress terminal differentiation of specific cell types during embryonic development. Specific AP-2 family members differ in their expression patterns and binding affinity for different promoters. This protein functions as both a transcriptional activator and repressor. Mutations in this gene result in autosomal dominant Char syndrome, suggesting that this gene functions in the differentiation of neural crest cell derivatives. [provided by RefSeq, Jul 2008]

TFAP2B Gene-Disease associations (from GenCC):

• Char syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• familial patent arterial duct

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 6-50823875-A-G is Benign according to our data. Variant chr6-50823875-A-G is described in CliVar as Benign. Clinvar id is 258984.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-50823875-A-G is described in CliVar as Benign. Clinvar id is 258984.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-50823875-A-G is described in CliVar as Benign. Clinvar id is 258984.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TFAP2B	NM_003221.4	c.540+10A>G		intron_variant	Intron 2 of 6	ENST00000393655.4	NP_003212.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TFAP2B	ENST00000393655.4	c.540+10A>G		intron_variant	Intron 2 of 6	1	NM_003221.4	ENSP00000377265.2
TFAP2B	ENST00000344788.7	c.534+10A>G		intron_variant	Intron 3 of 3	3		ENSP00000342252.3
TFAP2B	ENST00000489228.1	n.*10A>G		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 46394 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

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

GnomAD2 exomes AF: 0.000150 AC: 20 AN: 133470 AF XY: 0.000165

Gnomad AFR exome AF: 0.000158

Gnomad AMR exome AF: 0.0000408

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000134

Gnomad NFE exome AF: 0.000340

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000593 AC: 33 AN: 556464 Hom.: 1 Cov.: 0 AF XY: 0.0000621 AC XY: 17 AN XY: 273554

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 2064

American (AMR) AF: 0.0000557 AC: 1 AN: 17940

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8356

East Asian (EAS) AF: 0.00 AC: 0 AN: 16614

South Asian (SAS) AF: 0.0000362 AC: 1 AN: 27654

European-Finnish (FIN) AF: 0.000212 AC: 3 AN: 14132

Middle Eastern (MID) AF: 0.00126 AC: 2 AN: 1586

European-Non Finnish (NFE) AF: 0.0000537 AC: 24 AN: 446526

Other (OTH) AF: 0.0000926 AC: 2 AN: 21592

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 46394 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 22746

African (AFR) AF: 0.00 AC: 0 AN: 2824

American (AMR) AF: 0.00 AC: 0 AN: 6056

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1082

East Asian (EAS) AF: 0.00 AC: 0 AN: 2302

South Asian (SAS) AF: 0.00 AC: 0 AN: 1678

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3684

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 86

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 27634

Other (OTH) AF: 0.00 AC: 0 AN: 628

Alfa AF: 0.00325 Hom.: 3

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	11
DANN	Benign	0.66
PhyloP100		-0.010
Mutation Taster		=100/0	polymorphism (auto)

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: rs72890675; hg19: chr6-50791588;