4-78466288-C-T

Variant names:

• chr4-78466288-C-T
• rs7660664
• NM_025074.7:c.7110C>T

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.7110C>T​(p.His2370His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.348 in 1,613,504 control chromosomes in the GnomAD database, including 100,913 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (11113 hom., cov: 32)
  • Exomes 𝑓: 0.35 (89800 hom.)
• Consequence: FRAS1 NM_025074.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0430
• Publications: 18 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=0.022).
• BP6: Variant 4-78466288-C-T is Benign according to our data. Variant chr4-78466288-C-T is described in ClinVar as Benign. ClinVar VariationId is 261812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.043 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.48 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.7110C>T	p.His2370His	synonymous	Exon 50 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.7110C>T	p.His2370His	synonymous	Exon 50 of 74	ENSP00000422834.2	Q86XX4-2
	FRAS1	ENST00000682513.1		c.7110C>T	p.His2370His	synonymous	Exon 50 of 64	ENSP00000508201.1	A0A804HL50
	FRAS1	ENST00000915768.1		c.7029+1705C>T		intron	N/A	ENSP00000585827.1

Frequencies

GnomAD3 genomes AF: 0.373 AC: 56744 AN: 151962 Hom.: 11097 Cov.: 32

Gnomad AFR AF: 0.486

Gnomad AMI AF: 0.287

Gnomad AMR AF: 0.303

Gnomad ASJ AF: 0.340

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.311

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.359

Gnomad OTH AF: 0.370

GnomAD2 exomes AF: 0.311 AC: 77544 AN: 249080 AF XY: 0.306

Gnomad AFR exome AF: 0.488

Gnomad AMR exome AF: 0.222

Gnomad ASJ exome AF: 0.346

Gnomad EAS exome AF: 0.226

Gnomad FIN exome AF: 0.313

Gnomad NFE exome AF: 0.360

Gnomad OTH exome AF: 0.318

GnomAD4 exome AF: 0.346 AC: 505158 AN: 1461424 Hom.: 89800 Cov.: 44 AF XY: 0.340 AC XY: 247057 AN XY: 727012

African (AFR) AF: 0.487 AC: 16294 AN: 33470

American (AMR) AF: 0.235 AC: 10515 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.338 AC: 8829 AN: 26128

East Asian (EAS) AF: 0.209 AC: 8297 AN: 39694

South Asian (SAS) AF: 0.183 AC: 15778 AN: 86248

European-Finnish (FIN) AF: 0.320 AC: 17108 AN: 53400

Middle Eastern (MID) AF: 0.312 AC: 1796 AN: 5762

European-Non Finnish (NFE) AF: 0.365 AC: 405574 AN: 1111640

Other (OTH) AF: 0.347 AC: 20967 AN: 60364

GnomAD4 genome AF: 0.373 AC: 56798 AN: 152080 Hom.: 11113 Cov.: 32 AF XY: 0.366 AC XY: 27217 AN XY: 74346

African (AFR) AF: 0.486 AC: 20159 AN: 41470

American (AMR) AF: 0.302 AC: 4625 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.340 AC: 1178 AN: 3466

East Asian (EAS) AF: 0.227 AC: 1175 AN: 5168

South Asian (SAS) AF: 0.177 AC: 853 AN: 4818

European-Finnish (FIN) AF: 0.311 AC: 3287 AN: 10582

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.359 AC: 24393 AN: 67970

Other (OTH) AF: 0.366 AC: 772 AN: 2110

Alfa AF: 0.374 Hom.: 5896

Bravo AF: 0.378

Asia WGS AF: 0.245 AC: 853 AN: 3478

EpiCase AF: 0.350

EpiControl AF: 0.360

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	3.6
DANN	Benign	0.35
PhyloP100		-0.043
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: rs7660664; hg19: chr4-79387442; COSMIC: COSV53606655;