rs12643573

Variant names:

• chr4-78439284-A-T
• rs12643573
• NM_025074.7:c.5529+220A>T

Variant summary

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

The NM_025074.7(FRAS1):​c.5529+220A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 152,248 control chromosomes in the GnomAD database, including 1,338 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 0.12 (1338 hom., cov: 33)
• Consequence: FRAS1 NM_025074.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.212
• Publications: 3 publications found

Genes affected

FRAS1 (HGNC:19185): (Fraser extracellular matrix complex subunit 1) This gene encodes an extracellular matrix protein that appears to function in the regulation of epidermal-basement membrane adhesion and organogenesis during development. Mutations in this gene cause Fraser syndrome, a multisystem malformation that can include craniofacial, urogenital and respiratory system abnormalities. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

FRAS1 Gene-Disease associations (from GenCC):

• Fraser syndrome

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Fraser syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• renal agenesis, unilateral

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.211 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRAS1	NM_025074.7	c.5529+220A>T		intron_variant	Intron 40 of 73	ENST00000512123.4	NP_079350.5
FRAS1	NM_001166133.2	c.5529+220A>T		intron_variant	Intron 40 of 41		NP_001159605.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRAS1	ENST00000512123.4	c.5529+220A>T		intron_variant	Intron 40 of 73	5	NM_025074.7	ENSP00000422834.2

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18694 AN: 152130 Hom.: 1339 Cov.: 33

Gnomad AFR AF: 0.0672

Gnomad AMI AF: 0.0846

Gnomad AMR AF: 0.131

Gnomad ASJ AF: 0.213

Gnomad EAS AF: 0.222

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.146

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.123 AC: 18692 AN: 152248 Hom.: 1338 Cov.: 33 AF XY: 0.124 AC XY: 9254 AN XY: 74440

African (AFR) AF: 0.0672 AC: 2793 AN: 41546

American (AMR) AF: 0.131 AC: 2001 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.213 AC: 740 AN: 3468

East Asian (EAS) AF: 0.222 AC: 1150 AN: 5180

South Asian (SAS) AF: 0.113 AC: 546 AN: 4824

European-Finnish (FIN) AF: 0.149 AC: 1578 AN: 10606

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.139 AC: 9438 AN: 68020

Other (OTH) AF: 0.144 AC: 305 AN: 2112

Alfa AF: 0.128 Hom.: 173

Bravo AF: 0.121

Asia WGS AF: 0.181 AC: 629 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	5.0
DANN	Benign	0.91
PhyloP100		0.21
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: rs12643573; hg19: chr4-79360438; COSMIC: COSV53632309;