chr4-78421957-G-A

Variant names:

• chr4-78421957-G-A
• rs78575519
• NM_025074.7:c.4635G>A

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.4635G>A​(p.Pro1545Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 1,612,866 control chromosomes in the GnomAD database, including 40,863 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. P1545P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.17 (2599 hom., cov: 30)
  • Exomes 𝑓: 0.22 (38264 hom.)
• Consequence: FRAS1 NM_025074.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.01
• Publications: 9 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=-0.85).
• BP6: Variant 4-78421957-G-A is Benign according to our data. Variant chr4-78421957-G-A is described in ClinVar as Benign. ClinVar VariationId is 261807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.01 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.235 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.4635G>A	p.Pro1545Pro	synonymous	Exon 34 of 74	NP_079350.5
	FRAS1	NM_001166133.2		c.4635G>A	p.Pro1545Pro	synonymous	Exon 34 of 42	NP_001159605.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRAS1	ENST00000512123.4	TSL:5 MANE Select	c.4635G>A	p.Pro1545Pro	synonymous	Exon 34 of 74	ENSP00000422834.2
	FRAS1	ENST00000325942.11	TSL:1	c.4635G>A	p.Pro1545Pro	synonymous	Exon 34 of 42	ENSP00000326330.6
	FRAS1	ENST00000915768.1		c.4635G>A	p.Pro1545Pro	synonymous	Exon 34 of 73	ENSP00000585827.1

Frequencies

GnomAD3 genomes AF: 0.173 AC: 26307 AN: 151726 Hom.: 2599 Cov.: 30

Gnomad AFR AF: 0.0959

Gnomad AMI AF: 0.212

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.00155

Gnomad SAS AF: 0.0819

Gnomad FIN AF: 0.199

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.238

Gnomad OTH AF: 0.170

GnomAD2 exomes AF: 0.177 AC: 43928 AN: 248534 AF XY: 0.175

Gnomad AFR exome AF: 0.0902

Gnomad AMR exome AF: 0.166

Gnomad ASJ exome AF: 0.138

Gnomad EAS exome AF: 0.000445

Gnomad FIN exome AF: 0.206

Gnomad NFE exome AF: 0.240

Gnomad OTH exome AF: 0.192

GnomAD4 exome AF: 0.220 AC: 320878 AN: 1461024 Hom.: 38264 Cov.: 34 AF XY: 0.215 AC XY: 156608 AN XY: 726762

African (AFR) AF: 0.0874 AC: 2925 AN: 33470

American (AMR) AF: 0.165 AC: 7366 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 3486 AN: 26116

East Asian (EAS) AF: 0.000504 AC: 20 AN: 39682

South Asian (SAS) AF: 0.0917 AC: 7898 AN: 86164

European-Finnish (FIN) AF: 0.212 AC: 11317 AN: 53372

Middle Eastern (MID) AF: 0.113 AC: 648 AN: 5760

European-Non Finnish (NFE) AF: 0.248 AC: 275690 AN: 1111406

Other (OTH) AF: 0.191 AC: 11528 AN: 60350

GnomAD4 genome AF: 0.173 AC: 26314 AN: 151842 Hom.: 2599 Cov.: 30 AF XY: 0.169 AC XY: 12537 AN XY: 74184

African (AFR) AF: 0.0956 AC: 3961 AN: 41438

American (AMR) AF: 0.176 AC: 2680 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 448 AN: 3470

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5146

South Asian (SAS) AF: 0.0824 AC: 394 AN: 4782

European-Finnish (FIN) AF: 0.199 AC: 2097 AN: 10530

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.238 AC: 16146 AN: 67922

Other (OTH) AF: 0.169 AC: 355 AN: 2104

Alfa AF: 0.208 Hom.: 1850

Bravo AF: 0.167

Asia WGS AF: 0.0470 AC: 165 AN: 3478

EpiCase AF: 0.220

EpiControl AF: 0.225

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Fraser syndrome 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.24
DANN	Benign	0.51
PhyloP100		-3.0
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: rs78575519; hg19: chr4-79343111;