4-78499716-C-G

Variant names:

• chr4-78499716-C-G
• rs7695038
• NM_025074.7:c.9116-5C>G

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.9116-5C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.469 in 1,610,338 control chromosomes in the GnomAD database, including 183,644 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 0.52 (21213 hom., cov: 33)
  • Exomes 𝑓: 0.46 (162431 hom.)
• Consequence: FRAS1 NM_025074.7 splice_region, intron
• Scores: Splicing: ADA: 0.3054
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.500
• Publications: 12 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=-0.72).
• BP6: Variant 4-78499716-C-G is Benign according to our data. Variant chr4-78499716-C-G is described in ClinVar as Benign. ClinVar VariationId is 261818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.697 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.9116-5C>G		splice_region intron	N/A	NP_079350.5

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRAS1	ENST00000512123.4	TSL:5 MANE Select	c.9116-5C>G		splice_region intron	N/A	ENSP00000422834.2
	FRAS1	ENST00000915768.1		c.8888-5C>G		splice_region intron	N/A	ENSP00000585827.1
	FRAS1	ENST00000682513.1		c.9116-5C>G		splice_region intron	N/A	ENSP00000508201.1

Frequencies

GnomAD3 genomes AF: 0.518 AC: 78625 AN: 151710 Hom.: 21196 Cov.: 33

Gnomad AFR AF: 0.646

Gnomad AMI AF: 0.453

Gnomad AMR AF: 0.474

Gnomad ASJ AF: 0.589

Gnomad EAS AF: 0.716

Gnomad SAS AF: 0.657

Gnomad FIN AF: 0.450

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.432

Gnomad OTH AF: 0.532

GnomAD2 exomes AF: 0.504 AC: 125065 AN: 248282 AF XY: 0.510

Gnomad AFR exome AF: 0.649

Gnomad AMR exome AF: 0.445

Gnomad ASJ exome AF: 0.593

Gnomad EAS exome AF: 0.713

Gnomad FIN exome AF: 0.441

Gnomad NFE exome AF: 0.431

Gnomad OTH exome AF: 0.503

GnomAD4 exome AF: 0.464 AC: 676227 AN: 1458512 Hom.: 162431 Cov.: 32 AF XY: 0.469 AC XY: 340474 AN XY: 725584

African (AFR) AF: 0.658 AC: 21976 AN: 33412

American (AMR) AF: 0.450 AC: 20103 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.596 AC: 15550 AN: 26086

East Asian (EAS) AF: 0.714 AC: 28331 AN: 39668

South Asian (SAS) AF: 0.654 AC: 56236 AN: 85996

European-Finnish (FIN) AF: 0.439 AC: 23417 AN: 53344

Middle Eastern (MID) AF: 0.619 AC: 3424 AN: 5532

European-Non Finnish (NFE) AF: 0.430 AC: 476686 AN: 1109600

Other (OTH) AF: 0.507 AC: 30504 AN: 60216

GnomAD4 genome AF: 0.518 AC: 78690 AN: 151826 Hom.: 21213 Cov.: 33 AF XY: 0.522 AC XY: 38712 AN XY: 74190

African (AFR) AF: 0.646 AC: 26749 AN: 41386

American (AMR) AF: 0.474 AC: 7235 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.589 AC: 2041 AN: 3468

East Asian (EAS) AF: 0.716 AC: 3686 AN: 5148

South Asian (SAS) AF: 0.656 AC: 3164 AN: 4822

European-Finnish (FIN) AF: 0.450 AC: 4723 AN: 10500

Middle Eastern (MID) AF: 0.647 AC: 189 AN: 292

European-Non Finnish (NFE) AF: 0.432 AC: 29370 AN: 67924

Other (OTH) AF: 0.532 AC: 1122 AN: 2110

Alfa AF: 0.424 Hom.: 4006

Bravo AF: 0.524

EpiCase AF: 0.459

EpiControl AF: 0.459

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	-0.72
CADD	Benign	6.1
DANN	Benign	0.66
PhyloP100		0.50
Mutation Taster		=91/9	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.31
dbscSNV1_RF	Benign	0.14
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: rs7695038; hg19: chr4-79420870;