chr4-78482528-C-T

Variant names:

• chr4-78482528-C-T
• rs41327848
• NM_025074.7:c.8745C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_025074.7(FRAS1):​c.8745C>T​(p.Phe2915Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 1,612,948 control chromosomes in the GnomAD database, including 37,424 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4207 hom., cov: 33)
  • Exomes 𝑓: 0.20 (33217 hom.)
• Consequence: FRAS1 NM_025074.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.18
• Publications: 10 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.138).
• BP6: Variant 4-78482528-C-T is Benign according to our data. Variant chr4-78482528-C-T is described in ClinVar as Benign. ClinVar VariationId is 261816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.18 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.323 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025074.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRAS1	NM_025074.7	MANE Select	c.8745C>T	p.Phe2915Phe	synonymous	Exon 58 of 74	NP_079350.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRAS1	ENST00000512123.4	TSL:5 MANE Select	c.8745C>T	p.Phe2915Phe	synonymous	Exon 58 of 74	ENSP00000422834.2	Q86XX4-2
	FRAS1	ENST00000915768.1		c.8517C>T	p.Phe2839Phe	synonymous	Exon 57 of 73	ENSP00000585827.1
	FRAS1	ENST00000682513.1		c.8745C>T	p.Phe2915Phe	synonymous	Exon 58 of 64	ENSP00000508201.1	A0A804HL50

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33423 AN: 152012 Hom.: 4204 Cov.: 33

Gnomad AFR AF: 0.327

Gnomad AMI AF: 0.203

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.00366

Gnomad SAS AF: 0.0569

Gnomad FIN AF: 0.158

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.214

Gnomad OTH AF: 0.198

GnomAD2 exomes AF: 0.163 AC: 40480 AN: 248552 AF XY: 0.159

Gnomad AFR exome AF: 0.331

Gnomad AMR exome AF: 0.0937

Gnomad ASJ exome AF: 0.128

Gnomad EAS exome AF: 0.00245

Gnomad FIN exome AF: 0.162

Gnomad NFE exome AF: 0.216

Gnomad OTH exome AF: 0.169

GnomAD4 exome AF: 0.203 AC: 296670 AN: 1460818 Hom.: 33217 Cov.: 34 AF XY: 0.198 AC XY: 143856 AN XY: 726656

African (AFR) AF: 0.326 AC: 10899 AN: 33460

American (AMR) AF: 0.102 AC: 4533 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 3273 AN: 26122

East Asian (EAS) AF: 0.00239 AC: 95 AN: 39684

South Asian (SAS) AF: 0.0643 AC: 5530 AN: 86000

European-Finnish (FIN) AF: 0.165 AC: 8796 AN: 53394

Middle Eastern (MID) AF: 0.113 AC: 652 AN: 5764

European-Non Finnish (NFE) AF: 0.226 AC: 251662 AN: 1111396

Other (OTH) AF: 0.186 AC: 11230 AN: 60354

GnomAD4 genome AF: 0.220 AC: 33457 AN: 152130 Hom.: 4207 Cov.: 33 AF XY: 0.212 AC XY: 15761 AN XY: 74388

African (AFR) AF: 0.327 AC: 13565 AN: 41466

American (AMR) AF: 0.152 AC: 2330 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 425 AN: 3470

East Asian (EAS) AF: 0.00367 AC: 19 AN: 5184

South Asian (SAS) AF: 0.0568 AC: 274 AN: 4826

European-Finnish (FIN) AF: 0.158 AC: 1676 AN: 10578

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.214 AC: 14542 AN: 67994

Other (OTH) AF: 0.196 AC: 415 AN: 2116

Alfa AF: 0.217 Hom.: 2557

Bravo AF: 0.223

Asia WGS AF: 0.0560 AC: 197 AN: 3478

EpiCase AF: 0.200

EpiControl AF: 0.206

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Fraser syndrome 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	10
DANN	Benign	0.79
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs41327848; hg19: chr4-79403682; COSMIC: COSV53608178;