rs548267943

Variant names:

• chr4-78237493-CT-C
• rs548267943
• NM_025074.7:c.109-15delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_025074.7(FRAS1):​c.109-15delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,584,726 control chromosomes in the GnomAD database, including 113 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0083 (6 hom., cov: 32)
  • Exomes 𝑓: 0.011 (107 hom.)
• Consequence: FRAS1 NM_025074.7 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.377
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 4-78237493-CT-C is Benign according to our data. Variant chr4-78237493-CT-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261800.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00832 (1267/152202) while in subpopulation NFE AF = 0.0127 (864/68004). AF 95% confidence interval is 0.012. There are 6 homozygotes in GnomAd4. There are 629 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR,AD gene

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.109-15delT		intron	N/A	NP_079350.5
	FRAS1	NM_001166133.2		c.109-15delT		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.109-15delT		intron	N/A	ENSP00000422834.2
	FRAS1	ENST00000325942.11	TSL:1	c.109-15delT		intron	N/A	ENSP00000326330.6
	FRAS1	ENST00000508900.2	TSL:1	c.109-15delT		intron	N/A	ENSP00000423809.2

Frequencies

GnomAD3 genomes AF: 0.00832 AC: 1265 AN: 152084 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00212

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00387

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00270

Gnomad FIN AF: 0.0174

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0127

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.00932 AC: 2317 AN: 248640 AF XY: 0.00951

Gnomad AFR exome AF: 0.00162

Gnomad AMR exome AF: 0.00332

Gnomad ASJ exome AF: 0.00946

Gnomad EAS exome AF: 0.000223

Gnomad FIN exome AF: 0.0153

Gnomad NFE exome AF: 0.0144

Gnomad OTH exome AF: 0.00797

GnomAD4 exome AF: 0.0108 AC: 15495 AN: 1432524 Hom.: 107 Cov.: 25 AF XY: 0.0107 AC XY: 7617 AN XY: 714582

African (AFR) AF: 0.00173 AC: 57 AN: 32864

American (AMR) AF: 0.00336 AC: 150 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.00926 AC: 240 AN: 25924

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39512

South Asian (SAS) AF: 0.00302 AC: 258 AN: 85472

European-Finnish (FIN) AF: 0.0155 AC: 828 AN: 53346

Middle Eastern (MID) AF: 0.00385 AC: 22 AN: 5714

European-Non Finnish (NFE) AF: 0.0124 AC: 13415 AN: 1085650

Other (OTH) AF: 0.00877 AC: 521 AN: 59422

GnomAD4 genome AF: 0.00832 AC: 1267 AN: 152202 Hom.: 6 Cov.: 32 AF XY: 0.00845 AC XY: 629 AN XY: 74418

African (AFR) AF: 0.00212 AC: 88 AN: 41544

American (AMR) AF: 0.00386 AC: 59 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 47 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00291 AC: 14 AN: 4810

European-Finnish (FIN) AF: 0.0174 AC: 184 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0127 AC: 864 AN: 68004

Other (OTH) AF: 0.00474 AC: 10 AN: 2110

Alfa AF: 0.0102 Hom.: 4

Bravo AF: 0.00727

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.38
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs548267943; hg19: chr4-79158647;