4-78534560-C-G

Variant names:

• chr4-78534560-C-G
• rs4975070
• NM_025074.7:c.11037C>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_025074.7(FRAS1):​c.11037C>G​(p.Pro3679Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.455 in 1,608,114 control chromosomes in the GnomAD database, including 173,625 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. P3679P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.43 (15028 hom., cov: 33)
  • Exomes 𝑓: 0.46 (158597 hom.)
• Consequence: FRAS1 NM_025074.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.527
• Publications: 24 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.023).
• BP6: Variant 4-78534560-C-G is Benign according to our data. Variant chr4-78534560-C-G is described in ClinVar as Benign. ClinVar VariationId is 261801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.527 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.774 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.11037C>G	p.Pro3679Pro	synonymous	Exon 71 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.11037C>G	p.Pro3679Pro	synonymous	Exon 71 of 74	ENSP00000422834.2	Q86XX4-2
	FRAS1	ENST00000915768.1		c.10809C>G	p.Pro3603Pro	synonymous	Exon 70 of 73	ENSP00000585827.1

Frequencies

GnomAD3 genomes AF: 0.434 AC: 65985 AN: 151966 Hom.: 15032 Cov.: 33

Gnomad AFR AF: 0.345

Gnomad AMI AF: 0.348

Gnomad AMR AF: 0.466

Gnomad ASJ AF: 0.573

Gnomad EAS AF: 0.794

Gnomad SAS AF: 0.650

Gnomad FIN AF: 0.443

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.430

Gnomad OTH AF: 0.466

GnomAD2 exomes AF: 0.491 AC: 121945 AN: 248578 AF XY: 0.500

Gnomad AFR exome AF: 0.338

Gnomad AMR exome AF: 0.469

Gnomad ASJ exome AF: 0.579

Gnomad EAS exome AF: 0.791

Gnomad FIN exome AF: 0.437

Gnomad NFE exome AF: 0.430

Gnomad OTH exome AF: 0.493

GnomAD4 exome AF: 0.458 AC: 666415 AN: 1456030 Hom.: 158597 Cov.: 34 AF XY: 0.464 AC XY: 336141 AN XY: 724566

African (AFR) AF: 0.348 AC: 11588 AN: 33328

American (AMR) AF: 0.470 AC: 20953 AN: 44624

Ashkenazi Jewish (ASJ) AF: 0.582 AC: 15182 AN: 26066

East Asian (EAS) AF: 0.782 AC: 31021 AN: 39652

South Asian (SAS) AF: 0.645 AC: 55545 AN: 86058

European-Finnish (FIN) AF: 0.435 AC: 23190 AN: 53368

Middle Eastern (MID) AF: 0.571 AC: 3287 AN: 5760

European-Non Finnish (NFE) AF: 0.430 AC: 476322 AN: 1107006

Other (OTH) AF: 0.487 AC: 29327 AN: 60168

GnomAD4 genome AF: 0.434 AC: 66005 AN: 152084 Hom.: 15028 Cov.: 33 AF XY: 0.441 AC XY: 32757 AN XY: 74346

African (AFR) AF: 0.345 AC: 14304 AN: 41480

American (AMR) AF: 0.466 AC: 7117 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.573 AC: 1990 AN: 3472

East Asian (EAS) AF: 0.794 AC: 4108 AN: 5172

South Asian (SAS) AF: 0.650 AC: 3131 AN: 4820

European-Finnish (FIN) AF: 0.443 AC: 4674 AN: 10552

Middle Eastern (MID) AF: 0.571 AC: 168 AN: 294

European-Non Finnish (NFE) AF: 0.430 AC: 29212 AN: 67992

Other (OTH) AF: 0.466 AC: 984 AN: 2110

Alfa AF: 0.404 Hom.: 3842

Bravo AF: 0.431

Asia WGS AF: 0.675 AC: 2345 AN: 3478

EpiCase AF: 0.452

EpiControl AF: 0.454

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Fraser syndrome 1 (3)
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	9.3
DANN	Benign	0.67
PhyloP100		0.53
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4975070; hg19: chr4-79455714; COSMIC: COSV53609652;