chr4-78363685-A-G

Variant names:

• chr4-78363685-A-G
• rs80008695
• NM_025074.7:c.2575+20A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_025074.7(FRAS1):​c.2575+20A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,414,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FRAS1 NM_025074.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.479
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).

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.2575+20A>G		intron	N/A	NP_079350.5
	FRAS1	NM_001166133.2		c.2575+20A>G		intron	N/A	NP_001159605.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRAS1	ENST00000512123.4	TSL:5 MANE Select	c.2575+20A>G		intron	N/A	ENSP00000422834.2
	FRAS1	ENST00000325942.11	TSL:1	c.2575+20A>G		intron	N/A	ENSP00000326330.6
	FRAS1	ENST00000915768.1		c.2575+20A>G		intron	N/A	ENSP00000585827.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000113 AC: 2 AN: 176542 AF XY: 0.0000107

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000383

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000811

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1414174 Hom.: 0 Cov.: 32 AF XY: 0.00000143 AC XY: 1 AN XY: 698798

African (AFR) AF: 0.00 AC: 0 AN: 32254

American (AMR) AF: 0.0000268 AC: 1 AN: 37288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25302

East Asian (EAS) AF: 0.0000271 AC: 1 AN: 36966

South Asian (SAS) AF: 0.00 AC: 0 AN: 80180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50434

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1087252

Other (OTH) AF: 0.00 AC: 0 AN: 58786

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.7
DANN	Benign	0.74
PhyloP100		-0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs80008695; hg19: chr4-79284839;