chr4-78464565-G-A

Variant names:

• chr4-78464565-G-A
• rs6851427
• NM_025074.7:c.7011G>A

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.7011G>A​(p.Ala2337Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.364 in 1,613,104 control chromosomes in the GnomAD database, including 109,444 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. A2337A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.33 (8800 hom., cov: 31)
  • Exomes 𝑓: 0.37 (100644 hom.)
• Consequence: FRAS1 NM_025074.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.52
• Publications: 21 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=0.031).
• BP6: Variant 4-78464565-G-A is Benign according to our data. Variant chr4-78464565-G-A is described in ClinVar as Benign. ClinVar VariationId is 261811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.53 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.399 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.7011G>A	p.Ala2337Ala	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.7011G>A	p.Ala2337Ala	synonymous	Exon 49 of 74	ENSP00000422834.2	Q86XX4-2
	FRAS1	ENST00000915768.1		c.7011G>A	p.Ala2337Ala	synonymous	Exon 49 of 73	ENSP00000585827.1
	FRAS1	ENST00000682513.1		c.7011G>A	p.Ala2337Ala	synonymous	Exon 49 of 64	ENSP00000508201.1	A0A804HL50

Frequencies

GnomAD3 genomes AF: 0.326 AC: 49493 AN: 151860 Hom.: 8787 Cov.: 31

Gnomad AFR AF: 0.179

Gnomad AMI AF: 0.380

Gnomad AMR AF: 0.407

Gnomad ASJ AF: 0.334

Gnomad EAS AF: 0.295

Gnomad SAS AF: 0.303

Gnomad FIN AF: 0.436

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.383

Gnomad OTH AF: 0.332

GnomAD2 exomes AF: 0.371 AC: 92053 AN: 248356 AF XY: 0.366

Gnomad AFR exome AF: 0.169

Gnomad AMR exome AF: 0.474

Gnomad ASJ exome AF: 0.328

Gnomad EAS exome AF: 0.311

Gnomad FIN exome AF: 0.441

Gnomad NFE exome AF: 0.386

Gnomad OTH exome AF: 0.351

GnomAD4 exome AF: 0.367 AC: 536916 AN: 1461126 Hom.: 100644 Cov.: 41 AF XY: 0.366 AC XY: 266054 AN XY: 726828

African (AFR) AF: 0.173 AC: 5774 AN: 33466

American (AMR) AF: 0.463 AC: 20708 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.330 AC: 8630 AN: 26132

East Asian (EAS) AF: 0.306 AC: 12139 AN: 39670

South Asian (SAS) AF: 0.305 AC: 26274 AN: 86218

European-Finnish (FIN) AF: 0.443 AC: 23651 AN: 53350

Middle Eastern (MID) AF: 0.283 AC: 1630 AN: 5756

European-Non Finnish (NFE) AF: 0.376 AC: 417528 AN: 1111516

Other (OTH) AF: 0.341 AC: 20582 AN: 60336

GnomAD4 genome AF: 0.326 AC: 49534 AN: 151978 Hom.: 8800 Cov.: 31 AF XY: 0.329 AC XY: 24410 AN XY: 74258

African (AFR) AF: 0.179 AC: 7423 AN: 41442

American (AMR) AF: 0.407 AC: 6214 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.334 AC: 1160 AN: 3470

East Asian (EAS) AF: 0.295 AC: 1518 AN: 5146

South Asian (SAS) AF: 0.303 AC: 1460 AN: 4816

European-Finnish (FIN) AF: 0.436 AC: 4602 AN: 10560

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.383 AC: 26031 AN: 67972

Other (OTH) AF: 0.335 AC: 709 AN: 2114

Alfa AF: 0.356 Hom.: 30593

Bravo AF: 0.320

Asia WGS AF: 0.306 AC: 1067 AN: 3476

EpiCase AF: 0.367

EpiControl AF: 0.362

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Fraser syndrome 1 (3)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.27
DANN	Benign	0.71
PhyloP100		-2.5
Mutation Taster		=90/10	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: rs6851427; hg19: chr4-79385719; COSMIC: COSV53590139;