chr4-78464478-C-T

Variant names:

• chr4-78464478-C-T
• rs13123710
• NM_025074.7:c.6924C>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.6924C>T​(p.Val2308Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0736 in 1,613,782 control chromosomes in the GnomAD database, including 5,030 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V2308V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.055 (325 hom., cov: 32)
  • Exomes 𝑓: 0.075 (4705 hom.)
• Consequence: FRAS1 NM_025074.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.79
• Publications: 8 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 (BayesDel_noAF=-0.32).
• BP6: Variant 4-78464478-C-T is Benign according to our data. Variant chr4-78464478-C-T is described in ClinVar as Benign. ClinVar VariationId is 261810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.79 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0819 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.6924C>T	p.Val2308Val	synonymous	Exon 49 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.6924C>T	p.Val2308Val	synonymous	Exon 49 of 74	ENSP00000422834.2	Q86XX4-2
	FRAS1	ENST00000915768.1		c.6924C>T	p.Val2308Val	synonymous	Exon 49 of 73	ENSP00000585827.1
	FRAS1	ENST00000682513.1		c.6924C>T	p.Val2308Val	synonymous	Exon 49 of 64	ENSP00000508201.1	A0A804HL50

Frequencies

GnomAD3 genomes AF: 0.0552 AC: 8393 AN: 152126 Hom.: 326 Cov.: 32

Gnomad AFR AF: 0.0151

Gnomad AMI AF: 0.0747

Gnomad AMR AF: 0.0419

Gnomad ASJ AF: 0.0550

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0280

Gnomad FIN AF: 0.0888

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0837

Gnomad OTH AF: 0.0411

GnomAD2 exomes AF: 0.0575 AC: 14312 AN: 248878 AF XY: 0.0582

Gnomad AFR exome AF: 0.0117

Gnomad AMR exome AF: 0.0229

Gnomad ASJ exome AF: 0.0541

Gnomad EAS exome AF: 0.000278

Gnomad FIN exome AF: 0.0940

Gnomad NFE exome AF: 0.0849

Gnomad OTH exome AF: 0.0536

GnomAD4 exome AF: 0.0755 AC: 110315 AN: 1461538 Hom.: 4705 Cov.: 32 AF XY: 0.0742 AC XY: 53939 AN XY: 727068

African (AFR) AF: 0.0104 AC: 349 AN: 33478

American (AMR) AF: 0.0244 AC: 1093 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0558 AC: 1457 AN: 26134

East Asian (EAS) AF: 0.000378 AC: 15 AN: 39698

South Asian (SAS) AF: 0.0297 AC: 2558 AN: 86248

European-Finnish (FIN) AF: 0.0937 AC: 5003 AN: 53396

Middle Eastern (MID) AF: 0.0231 AC: 133 AN: 5766

European-Non Finnish (NFE) AF: 0.0862 AC: 95867 AN: 1111724

Other (OTH) AF: 0.0636 AC: 3840 AN: 60372

GnomAD4 genome AF: 0.0551 AC: 8391 AN: 152244 Hom.: 325 Cov.: 32 AF XY: 0.0539 AC XY: 4009 AN XY: 74432

African (AFR) AF: 0.0150 AC: 625 AN: 41534

American (AMR) AF: 0.0418 AC: 640 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0550 AC: 191 AN: 3470

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5188

South Asian (SAS) AF: 0.0278 AC: 134 AN: 4826

European-Finnish (FIN) AF: 0.0888 AC: 941 AN: 10594

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0837 AC: 5694 AN: 68006

Other (OTH) AF: 0.0407 AC: 86 AN: 2114

Alfa AF: 0.0687 Hom.: 683

Bravo AF: 0.0494

Asia WGS AF: 0.0110 AC: 37 AN: 3478

EpiCase AF: 0.0739

EpiControl AF: 0.0756

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	-0.32
CADD	Benign	8.5
DANN	Benign	0.65
PhyloP100		2.8
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs13123710; hg19: chr4-79385632; COSMIC: COSV53626018;