10-88991152-C-T

Variant names:

• chr10-88991152-C-T
• rs12775501
• NM_000043.6:c.30+246C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000043.6(FAS):​c.30+246C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.369 in 602,490 control chromosomes in the GnomAD database, including 42,817 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8861 hom., cov: 33)
  • Exomes 𝑓: 0.38 (33956 hom.)
• Consequence: FAS NM_000043.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.43
• Publications: 19 publications found

Genes affected

FAS (HGNC:11920): (Fas cell surface death receptor) The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor contains a death domain. It has been shown to play a central role in the physiological regulation of programmed cell death, and has been implicated in the pathogenesis of various malignancies and diseases of the immune system. The interaction of this receptor with its ligand allows the formation of a death-inducing signaling complex that includes Fas-associated death domain protein (FADD), caspase 8, and caspase 10. The autoproteolytic processing of the caspases in the complex triggers a downstream caspase cascade, and leads to apoptosis. This receptor has been also shown to activate NF-kappaB, MAPK3/ERK1, and MAPK8/JNK, and is found to be involved in transducing the proliferating signals in normal diploid fibroblast and T cells. Several alternatively spliced transcript variants have been described, some of which are candidates for nonsense-mediated mRNA decay (NMD). The isoforms lacking the transmembrane domain may negatively regulate the apoptosis mediated by the full length isoform. [provided by RefSeq, Mar 2011]

ENSG00000286116 (HGNC:):

ACTA2 (HGNC:130): (actin alpha 2, smooth muscle) This gene encodes one of six different actin proteins. Actins are highly conserved proteins that are involved in cell motility, structure, integrity, and intercellular signaling. The encoded protein is a smooth muscle actin that is involved in vascular contractility and blood pressure homeostasis. Mutations in this gene cause a variety of vascular diseases, such as thoracic aortic disease, coronary artery disease, stroke, and Moyamoya disease, as well as multisystemic smooth muscle dysfunction syndrome. [provided by RefSeq, Sep 2017]

ACTA2 Gene-Disease associations (from GenCC):

• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• multisystemic smooth muscle dysfunction syndrome

  Inheritance: AD, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• aortic aneurysm, familial thoracic 6

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
• Moyamoya disease 5

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, G2P
• connective tissue disorder

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 10-88991152-C-T is Benign according to our data. Variant chr10-88991152-C-T is described in ClinVar as [Benign]. Clinvar id is 1284170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.505 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAS	NM_000043.6	c.30+246C>T		intron_variant	Intron 1 of 8	ENST00000652046.1	NP_000034.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAS	ENST00000652046.1	c.30+246C>T		intron_variant	Intron 1 of 8		NM_000043.6	ENSP00000498466.1

Frequencies

GnomAD3 genomes AF: 0.329 AC: 49998 AN: 152022 Hom.: 8861 Cov.: 33

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.422

Gnomad AMR AF: 0.353

Gnomad ASJ AF: 0.433

Gnomad EAS AF: 0.521

Gnomad SAS AF: 0.441

Gnomad FIN AF: 0.381

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.366

Gnomad OTH AF: 0.349

GnomAD4 exome AF: 0.383 AC: 172612 AN: 450350 Hom.: 33956 Cov.: 4 AF XY: 0.389 AC XY: 93196 AN XY: 239662

African (AFR) AF: 0.197 AC: 2423 AN: 12316

American (AMR) AF: 0.352 AC: 6679 AN: 18958

Ashkenazi Jewish (ASJ) AF: 0.429 AC: 5803 AN: 13526

East Asian (EAS) AF: 0.499 AC: 15390 AN: 30860

South Asian (SAS) AF: 0.452 AC: 20982 AN: 46446

European-Finnish (FIN) AF: 0.396 AC: 11368 AN: 28712

Middle Eastern (MID) AF: 0.417 AC: 815 AN: 1954

European-Non Finnish (NFE) AF: 0.366 AC: 99412 AN: 271774

Other (OTH) AF: 0.377 AC: 9740 AN: 25804

GnomAD4 genome AF: 0.329 AC: 50002 AN: 152140 Hom.: 8861 Cov.: 33 AF XY: 0.334 AC XY: 24818 AN XY: 74390

African (AFR) AF: 0.196 AC: 8121 AN: 41504

American (AMR) AF: 0.353 AC: 5401 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.433 AC: 1502 AN: 3472

East Asian (EAS) AF: 0.521 AC: 2696 AN: 5172

South Asian (SAS) AF: 0.442 AC: 2135 AN: 4826

European-Finnish (FIN) AF: 0.381 AC: 4029 AN: 10586

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.366 AC: 24892 AN: 67970

Other (OTH) AF: 0.347 AC: 731 AN: 2106

Alfa AF: 0.348 Hom.: 2538

Bravo AF: 0.320

Asia WGS AF: 0.407 AC: 1415 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 62% of patients studied by a panel of primary immunodeficiencies. Number of patients: 59. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	4.2
DANN	Benign	0.92
PhyloP100		-2.4
PromoterAI		-0.043	Neutral
Mutation Taster		=299/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs12775501; hg19: chr10-90750909;