rs2867014

Variant names:

• chr4-78265017-G-A
• rs2867014
• NM_025074.7:c.604-8G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_025074.7(FRAS1):​c.604-8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.985 in 1,562,592 control chromosomes in the GnomAD database, including 759,364 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.94 (67717 hom., cov: 31)
  • Exomes 𝑓: 0.99 (691647 hom.)
• Consequence: FRAS1 NM_025074.7 splice_region, intron
• Scores: Splicing: ADA: 0.0007514
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0850
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 4-78265017-G-A is Benign according to our data. Variant chr4-78265017-G-A is described in ClinVar as Benign. ClinVar VariationId is 261808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.991 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.604-8G>A		splice_region intron	N/A	NP_079350.5
	FRAS1	NM_001166133.2		c.604-8G>A		splice_region intron	N/A	NP_001159605.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRAS1	ENST00000512123.4	TSL:5 MANE Select	c.604-8G>A		splice_region intron	N/A	ENSP00000422834.2
	FRAS1	ENST00000325942.11	TSL:1	c.604-8G>A		splice_region intron	N/A	ENSP00000326330.6
	FRAS1	ENST00000508900.2	TSL:1	c.604-8G>A		splice_region intron	N/A	ENSP00000423809.2

Frequencies

GnomAD3 genomes AF: 0.940 AC: 142943 AN: 152114 Hom.: 67676 Cov.: 31

Gnomad AFR AF: 0.804

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.974

Gnomad ASJ AF: 0.982

Gnomad EAS AF: 0.958

Gnomad SAS AF: 0.987

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.965

Gnomad NFE AF: 0.997

Gnomad OTH AF: 0.950

GnomAD2 exomes AF: 0.977 AC: 241753 AN: 247408 AF XY: 0.981

Gnomad AFR exome AF: 0.798

Gnomad AMR exome AF: 0.982

Gnomad ASJ exome AF: 0.981

Gnomad EAS exome AF: 0.949

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.997

Gnomad OTH exome AF: 0.981

GnomAD4 exome AF: 0.990 AC: 1395975 AN: 1410360 Hom.: 691647 Cov.: 23 AF XY: 0.990 AC XY: 697982 AN XY: 704850

African (AFR) AF: 0.795 AC: 25683 AN: 32312

American (AMR) AF: 0.981 AC: 43650 AN: 44514

Ashkenazi Jewish (ASJ) AF: 0.980 AC: 25310 AN: 25826

East Asian (EAS) AF: 0.958 AC: 37773 AN: 39434

South Asian (SAS) AF: 0.985 AC: 83469 AN: 84768

European-Finnish (FIN) AF: 1.00 AC: 53246 AN: 53248

Middle Eastern (MID) AF: 0.977 AC: 5549 AN: 5682

European-Non Finnish (NFE) AF: 0.998 AC: 1063890 AN: 1065902

Other (OTH) AF: 0.978 AC: 57405 AN: 58674

GnomAD4 genome AF: 0.940 AC: 143040 AN: 152232 Hom.: 67717 Cov.: 31 AF XY: 0.941 AC XY: 70064 AN XY: 74446

African (AFR) AF: 0.804 AC: 33354 AN: 41498

American (AMR) AF: 0.974 AC: 14897 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.982 AC: 3410 AN: 3472

East Asian (EAS) AF: 0.958 AC: 4952 AN: 5168

South Asian (SAS) AF: 0.987 AC: 4763 AN: 4826

European-Finnish (FIN) AF: 1.00 AC: 10618 AN: 10620

Middle Eastern (MID) AF: 0.963 AC: 283 AN: 294

European-Non Finnish (NFE) AF: 0.997 AC: 67842 AN: 68036

Other (OTH) AF: 0.950 AC: 2009 AN: 2114

Alfa AF: 0.969 Hom.: 48289

Bravo AF: 0.931

Asia WGS AF: 0.961 AC: 3342 AN: 3478

ClinVar

ClinVar submissions as Germline

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	2.6
DANN	Benign	0.33
PhyloP100		-0.085
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00075
dbscSNV1_RF	Benign	0.068
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: rs2867014; hg19: chr4-79186171; COSMIC: COSV53613407;