4-78534579-C-T

Variant names:

• chr4-78534579-C-T
• rs4975139
• NM_025074.7:c.11056C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_025074.7(FRAS1):​c.11056C>T​(p.Leu3686Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.455 in 1,607,578 control chromosomes in the GnomAD database, including 173,554 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (15019 hom., cov: 33)
  • Exomes 𝑓: 0.46 (158535 hom.)
• Consequence: FRAS1 NM_025074.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.15
• Publications: 22 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.013).
• BP6: Variant 4-78534579-C-T is Benign according to our data. Variant chr4-78534579-C-T is described in ClinVar as Benign. ClinVar VariationId is 261802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.15 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.774 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRAS1	NM_025074.7	MANE Select	c.11056C>T	p.Leu3686Leu	synonymous	Exon 71 of 74	NP_079350.5

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRAS1	ENST00000512123.4	TSL:5 MANE Select	c.11056C>T	p.Leu3686Leu	synonymous	Exon 71 of 74	ENSP00000422834.2

Frequencies

GnomAD3 genomes AF: 0.434 AC: 65967 AN: 151988 Hom.: 15023 Cov.: 33

Gnomad AFR AF: 0.345

Gnomad AMI AF: 0.348

Gnomad AMR AF: 0.466

Gnomad ASJ AF: 0.574

Gnomad EAS AF: 0.794

Gnomad SAS AF: 0.650

Gnomad FIN AF: 0.443

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.429

Gnomad OTH AF: 0.466

GnomAD2 exomes AF: 0.490 AC: 121714 AN: 248288 AF XY: 0.500

Gnomad AFR exome AF: 0.338

Gnomad AMR exome AF: 0.468

Gnomad ASJ exome AF: 0.578

Gnomad EAS exome AF: 0.791

Gnomad FIN exome AF: 0.437

Gnomad NFE exome AF: 0.429

Gnomad OTH exome AF: 0.492

GnomAD4 exome AF: 0.458 AC: 666087 AN: 1455472 Hom.: 158535 Cov.: 34 AF XY: 0.464 AC XY: 336008 AN XY: 724348

African (AFR) AF: 0.348 AC: 11593 AN: 33338

American (AMR) AF: 0.469 AC: 20919 AN: 44574

Ashkenazi Jewish (ASJ) AF: 0.583 AC: 15173 AN: 26046

East Asian (EAS) AF: 0.782 AC: 31010 AN: 39632

South Asian (SAS) AF: 0.645 AC: 55472 AN: 85962

European-Finnish (FIN) AF: 0.435 AC: 23184 AN: 53354

Middle Eastern (MID) AF: 0.571 AC: 3284 AN: 5754

European-Non Finnish (NFE) AF: 0.430 AC: 476141 AN: 1106666

Other (OTH) AF: 0.487 AC: 29311 AN: 60146

GnomAD4 genome AF: 0.434 AC: 65987 AN: 152106 Hom.: 15019 Cov.: 33 AF XY: 0.441 AC XY: 32756 AN XY: 74360

African (AFR) AF: 0.345 AC: 14303 AN: 41496

American (AMR) AF: 0.465 AC: 7114 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.574 AC: 1990 AN: 3468

East Asian (EAS) AF: 0.794 AC: 4105 AN: 5170

South Asian (SAS) AF: 0.649 AC: 3133 AN: 4824

European-Finnish (FIN) AF: 0.443 AC: 4677 AN: 10566

Middle Eastern (MID) AF: 0.571 AC: 168 AN: 294

European-Non Finnish (NFE) AF: 0.429 AC: 29194 AN: 67978

Other (OTH) AF: 0.466 AC: 986 AN: 2114

Alfa AF: 0.439 Hom.: 51333

Bravo AF: 0.431

Asia WGS AF: 0.675 AC: 2345 AN: 3478

EpiCase AF: 0.452

EpiControl AF: 0.454

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	4.4
DANN	Benign	0.64
PhyloP100		1.2
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: rs4975139; hg19: chr4-79455733; COSMIC: COSV53610394;