4-78451776-C-T

Variant names:

• chr4-78451776-C-T
• rs753752
• NM_025074.7:c.6468C>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.6468C>T​(p.His2156His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.707 in 1,599,366 control chromosomes in the GnomAD database, including 405,000 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (34511 hom., cov: 32)
  • Exomes 𝑓: 0.71 (370489 hom.)
• Consequence: FRAS1 NM_025074.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.32
• Publications: 20 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 (REVEL=0.009).
• BP6: Variant 4-78451776-C-T is Benign according to our data. Variant chr4-78451776-C-T is described in ClinVar as Benign. ClinVar VariationId is 197552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.32 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.737 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.6468C>T	p.His2156His	synonymous	Exon 46 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.6468C>T	p.His2156His	synonymous	Exon 46 of 74	ENSP00000422834.2	Q86XX4-2
	FRAS1	ENST00000915768.1		c.6468C>T	p.His2156His	synonymous	Exon 46 of 73	ENSP00000585827.1
	FRAS1	ENST00000682513.1		c.6468C>T	p.His2156His	synonymous	Exon 46 of 64	ENSP00000508201.1	A0A804HL50

Frequencies

GnomAD3 genomes AF: 0.667 AC: 101346 AN: 151884 Hom.: 34500 Cov.: 32

Gnomad AFR AF: 0.551

Gnomad AMI AF: 0.667

Gnomad AMR AF: 0.698

Gnomad ASJ AF: 0.669

Gnomad EAS AF: 0.523

Gnomad SAS AF: 0.483

Gnomad FIN AF: 0.750

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.742

Gnomad OTH AF: 0.671

GnomAD2 exomes AF: 0.676 AC: 161294 AN: 238600 AF XY: 0.668

Gnomad AFR exome AF: 0.541

Gnomad AMR exome AF: 0.689

Gnomad ASJ exome AF: 0.670

Gnomad EAS exome AF: 0.535

Gnomad FIN exome AF: 0.757

Gnomad NFE exome AF: 0.746

Gnomad OTH exome AF: 0.671

GnomAD4 exome AF: 0.711 AC: 1028905 AN: 1447364 Hom.: 370489 Cov.: 31 AF XY: 0.704 AC XY: 506861 AN XY: 719770

African (AFR) AF: 0.541 AC: 17654 AN: 32656

American (AMR) AF: 0.693 AC: 29310 AN: 42312

Ashkenazi Jewish (ASJ) AF: 0.664 AC: 17025 AN: 25658

East Asian (EAS) AF: 0.514 AC: 20351 AN: 39574

South Asian (SAS) AF: 0.492 AC: 41114 AN: 83550

European-Finnish (FIN) AF: 0.766 AC: 40546 AN: 52940

Middle Eastern (MID) AF: 0.593 AC: 3380 AN: 5702

European-Non Finnish (NFE) AF: 0.741 AC: 818865 AN: 1105226

Other (OTH) AF: 0.681 AC: 40660 AN: 59746

GnomAD4 genome AF: 0.667 AC: 101405 AN: 152002 Hom.: 34511 Cov.: 32 AF XY: 0.664 AC XY: 49301 AN XY: 74294

African (AFR) AF: 0.551 AC: 22829 AN: 41412

American (AMR) AF: 0.698 AC: 10672 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.669 AC: 2321 AN: 3468

East Asian (EAS) AF: 0.523 AC: 2697 AN: 5152

South Asian (SAS) AF: 0.483 AC: 2322 AN: 4812

European-Finnish (FIN) AF: 0.750 AC: 7926 AN: 10564

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

European-Non Finnish (NFE) AF: 0.742 AC: 50450 AN: 67982

Other (OTH) AF: 0.669 AC: 1412 AN: 2112

Alfa AF: 0.712 Hom.: 57485

Bravo AF: 0.661

Asia WGS AF: 0.539 AC: 1875 AN: 3478

EpiCase AF: 0.718

EpiControl AF: 0.724

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.059
DANN	Benign	0.27
PhyloP100		-2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs753752; hg19: chr4-79372930; COSMIC: COSV53606639; COSMIC: COSV53606639;