rs1801167

Variant names:

• chr5-128345430-G-A
• rs1801167
• NM_001999.4:c.3144C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-128345430-G-A
• chr5-128345430-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001999.4(FBN2):​c.3144C>T​(p.Tyr1048Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000284 in 1,614,118 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: FBN2 NM_001999.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0490
• Publications: 2 publications found

Genes affected

FBN2 (HGNC:3604): (fibrillin 2) The protein encoded by this gene is a component of connective tissue microfibrils and may be involved in elastic fiber assembly. Mutations in this gene cause congenital contractural arachnodactyly. [provided by RefSeq, Jul 2008]

FBN2 Gene-Disease associations (from GenCC):

• congenital contractural arachnodactyly

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• carpal tunnel syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Franklin by Genoox
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• macular degeneration, early-onset

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 5-128345430-G-A is Benign according to our data. Variant chr5-128345430-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 263905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.049 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000999 (152/152226) while in subpopulation AFR AF = 0.00303 (126/41536). AF 95% confidence interval is 0.0026. There are 1 homozygotes in GnomAd4. There are 64 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 152 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001999.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN2	NM_001999.4	MANE Select	c.3144C>T	p.Tyr1048Tyr	synonymous	Exon 24 of 65	NP_001990.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN2	ENST00000262464.9	TSL:1 MANE Select	c.3144C>T	p.Tyr1048Tyr	synonymous	Exon 24 of 65	ENSP00000262464.4
	FBN2	ENST00000508989.5	TSL:2	c.3045C>T	p.Tyr1015Tyr	synonymous	Exon 23 of 33	ENSP00000425596.1

Frequencies

GnomAD3 genomes AF: 0.000986 AC: 150 AN: 152108 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00299

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000298 AC: 75 AN: 251436 AF XY: 0.000302

Gnomad AFR exome AF: 0.00221

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000967

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000209 AC: 306 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.000194 AC XY: 141 AN XY: 727248

African (AFR) AF: 0.00352 AC: 118 AN: 33480

American (AMR) AF: 0.000246 AC: 11 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000574 AC: 15 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5768

European-Non Finnish (NFE) AF: 0.0000773 AC: 86 AN: 1112010

Other (OTH) AF: 0.000795 AC: 48 AN: 60396

GnomAD4 genome AF: 0.000999 AC: 152 AN: 152226 Hom.: 1 Cov.: 32 AF XY: 0.000860 AC XY: 64 AN XY: 74432

African (AFR) AF: 0.00303 AC: 126 AN: 41536

American (AMR) AF: 0.00105 AC: 16 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000831 AC: 4 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68008

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000812 Hom.: 0

Bravo AF: 0.000975

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Congenital contractural arachnodactyly (2)
-	-	2	not provided (2)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.7
DANN	Benign	0.38
PhyloP100		-0.049
Mutation Taster		=99/1	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: rs1801167; hg19: chr5-127681122; COSMIC: COSV52495789;