12-43796827-T-C

Variant names:

• chr12-43796827-T-C
• rs6582484
• NM_002822.5:c.882+149A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002822.5(TWF1):​c.882+149A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.166 in 768,710 control chromosomes in the GnomAD database, including 12,746 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.22 (4465 hom., cov: 32)
  • Exomes 𝑓: 0.15 (8281 hom.)
• Consequence: TWF1 NM_002822.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.353
• Publications: 10 publications found

Genes affected

TWF1 (HGNC:9620): (twinfilin actin binding protein 1) This gene encodes twinfilin, an actin monomer-binding protein conserved from yeast to mammals. Studies of the mouse counterpart suggest that this protein may be an actin monomer-binding protein, and its localization to cortical G-actin-rich structures may be regulated by the small GTPase RAC1. [provided by RefSeq, Jul 2008]

IRAK4 (HGNC:17967): (interleukin 1 receptor associated kinase 4) This gene encodes a kinase that activates NF-kappaB in both the Toll-like receptor (TLR) and T-cell receptor (TCR) signaling pathways. The protein is essential for most innate immune responses. Mutations in this gene result in IRAK4 deficiency and recurrent invasive pneumococcal disease. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

TMEM117 (HGNC:25308): (transmembrane protein 117) Involved in intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress. Located in endoplasmic reticulum and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.377 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TWF1	NM_002822.5	c.882+149A>G		intron_variant	Intron 8 of 8	ENST00000395510.7	NP_002813.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TWF1	ENST00000395510.7	c.882+149A>G		intron_variant	Intron 8 of 8	1	NM_002822.5	ENSP00000378886.2

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32647 AN: 151760 Hom.: 4449 Cov.: 32

Gnomad AFR AF: 0.381

Gnomad AMI AF: 0.0440

Gnomad AMR AF: 0.186

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.101

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.232

GnomAD4 exome AF: 0.154 AC: 94791 AN: 616832 Hom.: 8281 AF XY: 0.153 AC XY: 49649 AN XY: 324548

African (AFR) AF: 0.383 AC: 5629 AN: 14696

American (AMR) AF: 0.175 AC: 3324 AN: 18954

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 1768 AN: 15764

East Asian (EAS) AF: 0.105 AC: 3261 AN: 30976

South Asian (SAS) AF: 0.140 AC: 6890 AN: 49376

European-Finnish (FIN) AF: 0.104 AC: 4181 AN: 40050

Middle Eastern (MID) AF: 0.150 AC: 343 AN: 2290

European-Non Finnish (NFE) AF: 0.155 AC: 64248 AN: 413812

Other (OTH) AF: 0.166 AC: 5147 AN: 30914

GnomAD4 genome AF: 0.215 AC: 32703 AN: 151878 Hom.: 4465 Cov.: 32 AF XY: 0.210 AC XY: 15623 AN XY: 74256

African (AFR) AF: 0.382 AC: 15796 AN: 41390

American (AMR) AF: 0.185 AC: 2830 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 418 AN: 3466

East Asian (EAS) AF: 0.123 AC: 635 AN: 5182

South Asian (SAS) AF: 0.158 AC: 761 AN: 4808

European-Finnish (FIN) AF: 0.101 AC: 1071 AN: 10596

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.156 AC: 10614 AN: 67860

Other (OTH) AF: 0.229 AC: 482 AN: 2102

Alfa AF: 0.171 Hom.: 3513

Bravo AF: 0.226

Asia WGS AF: 0.149 AC: 519 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.8
DANN	Benign	0.66
PhyloP100		-0.35
Mutation Taster		=99/1	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: rs6582484; hg19: chr12-44190630;