4-78499857-G-T

Variant names:

• chr4-78499857-G-T
• rs11933630
• NM_025074.7:c.9252G>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.9252G>T​(p.Arg3084Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 1,613,000 control chromosomes in the GnomAD database, including 31,623 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R3084R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.14 (1897 hom., cov: 32)
  • Exomes 𝑓: 0.19 (29726 hom.)
• Consequence: FRAS1 NM_025074.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.172
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 4-78499857-G-T is Benign according to our data. Variant chr4-78499857-G-T is described in ClinVar as Benign. ClinVar VariationId is 261820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.172 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.204 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.9252G>T	p.Arg3084Arg	synonymous	Exon 61 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.9252G>T	p.Arg3084Arg	synonymous	Exon 61 of 74	ENSP00000422834.2
	FRAS1	ENST00000682513.1		c.9252G>T	p.Arg3084Arg	synonymous	Exon 61 of 64	ENSP00000508201.1

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21945 AN: 152092 Hom.: 1897 Cov.: 32

Gnomad AFR AF: 0.0817

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.00288

Gnomad SAS AF: 0.0530

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.207

Gnomad OTH AF: 0.139

GnomAD2 exomes AF: 0.140 AC: 34863 AN: 248832 AF XY: 0.140

Gnomad AFR exome AF: 0.0775

Gnomad AMR exome AF: 0.0787

Gnomad ASJ exome AF: 0.117

Gnomad EAS exome AF: 0.00167

Gnomad FIN exome AF: 0.155

Gnomad NFE exome AF: 0.210

Gnomad OTH exome AF: 0.157

GnomAD4 exome AF: 0.191 AC: 279029 AN: 1460790 Hom.: 29726 Cov.: 34 AF XY: 0.187 AC XY: 135687 AN XY: 726624

African (AFR) AF: 0.0783 AC: 2622 AN: 33470

American (AMR) AF: 0.0838 AC: 3747 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 2985 AN: 26114

East Asian (EAS) AF: 0.00209 AC: 83 AN: 39692

South Asian (SAS) AF: 0.0586 AC: 5050 AN: 86178

European-Finnish (FIN) AF: 0.157 AC: 8374 AN: 53380

Middle Eastern (MID) AF: 0.0948 AC: 546 AN: 5758

European-Non Finnish (NFE) AF: 0.221 AC: 245617 AN: 1111160

Other (OTH) AF: 0.166 AC: 10005 AN: 60324

GnomAD4 genome AF: 0.144 AC: 21945 AN: 152210 Hom.: 1897 Cov.: 32 AF XY: 0.138 AC XY: 10305 AN XY: 74426

African (AFR) AF: 0.0815 AC: 3383 AN: 41530

American (AMR) AF: 0.119 AC: 1814 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 386 AN: 3472

East Asian (EAS) AF: 0.00289 AC: 15 AN: 5190

South Asian (SAS) AF: 0.0529 AC: 255 AN: 4822

European-Finnish (FIN) AF: 0.149 AC: 1577 AN: 10592

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.207 AC: 14078 AN: 67990

Other (OTH) AF: 0.138 AC: 291 AN: 2110

Alfa AF: 0.176 Hom.: 4242

Bravo AF: 0.140

Asia WGS AF: 0.0360 AC: 126 AN: 3478

EpiCase AF: 0.194

EpiControl AF: 0.201

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	4.0
DANN	Benign	0.61
PhyloP100		-0.17
Mutation Taster		=98/2	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: rs11933630; hg19: chr4-79421011; COSMIC: COSV53592637;