4-78516001-C-T

Variant names:

• chr4-78516001-C-T
• rs3749487
• NM_025074.7:c.10377C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4 BP6_Very_Strong BP7 BA1

The NM_025074.7(FRAS1):​c.10377C>T​(p.Thr3459Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 1,611,934 control chromosomes in the GnomAD database, including 25,924 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. T3459T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.19 (2692 hom., cov: 32)
  • Exomes 𝑓: 0.18 (23232 hom.)
• Consequence: FRAS1 NM_025074.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.67
• Publications: 13 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.208).
• BP6: Variant 4-78516001-C-T is Benign according to our data. Variant chr4-78516001-C-T is described in ClinVar as Benign. ClinVar VariationId is 261795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.67 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.221 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.10377C>T	p.Thr3459Thr	synonymous	Exon 66 of 74	NP_079350.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRAS1	ENST00000512123.4	TSL:5 MANE Select	c.10377C>T	p.Thr3459Thr	synonymous	Exon 66 of 74	ENSP00000422834.2	Q86XX4-2
	FRAS1	ENST00000915768.1		c.10149C>T	p.Thr3383Thr	synonymous	Exon 65 of 73	ENSP00000585827.1

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28199 AN: 152072 Hom.: 2690 Cov.: 32

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.269

Gnomad EAS AF: 0.232

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.201

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.182

Gnomad OTH AF: 0.189

GnomAD2 exomes AF: 0.180 AC: 44314 AN: 246138 AF XY: 0.179

Gnomad AFR exome AF: 0.184

Gnomad AMR exome AF: 0.138

Gnomad ASJ exome AF: 0.265

Gnomad EAS exome AF: 0.235

Gnomad FIN exome AF: 0.200

Gnomad NFE exome AF: 0.183

Gnomad OTH exome AF: 0.173

GnomAD4 exome AF: 0.177 AC: 258534 AN: 1459744 Hom.: 23232 Cov.: 33 AF XY: 0.176 AC XY: 127810 AN XY: 725986

African (AFR) AF: 0.192 AC: 6422 AN: 33442

American (AMR) AF: 0.143 AC: 6395 AN: 44568

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 6821 AN: 26108

East Asian (EAS) AF: 0.212 AC: 8375 AN: 39590

South Asian (SAS) AF: 0.144 AC: 12392 AN: 85996

European-Finnish (FIN) AF: 0.205 AC: 10964 AN: 53356

Middle Eastern (MID) AF: 0.222 AC: 1279 AN: 5762

European-Non Finnish (NFE) AF: 0.175 AC: 194391 AN: 1110602

Other (OTH) AF: 0.191 AC: 11495 AN: 60320

GnomAD4 genome AF: 0.185 AC: 28208 AN: 152190 Hom.: 2692 Cov.: 32 AF XY: 0.186 AC XY: 13859 AN XY: 74408

African (AFR) AF: 0.186 AC: 7738 AN: 41514

American (AMR) AF: 0.169 AC: 2590 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.269 AC: 933 AN: 3472

East Asian (EAS) AF: 0.232 AC: 1198 AN: 5164

South Asian (SAS) AF: 0.140 AC: 677 AN: 4826

European-Finnish (FIN) AF: 0.201 AC: 2129 AN: 10594

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.182 AC: 12349 AN: 68004

Other (OTH) AF: 0.187 AC: 395 AN: 2112

Alfa AF: 0.176 Hom.: 2162

Bravo AF: 0.183

Asia WGS AF: 0.207 AC: 721 AN: 3478

ClinVar

ClinVar submissions

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	-0.51
CADD	Benign	0.28
DANN	Benign	0.45
PhyloP100		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	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: rs3749487; hg19: chr4-79437155; COSMIC: COSV53606678;