chr4-78479714-C-T

Variant names:

• chr4-78479714-C-T
• rs11098194
• NM_025074.7:c.8439C>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.8439C>T​(p.Asp2813Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.361 in 1,576,474 control chromosomes in the GnomAD database, including 106,007 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8800 hom., cov: 33)
  • Exomes 𝑓: 0.37 (97207 hom.)
• Consequence: FRAS1 NM_025074.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.37
• Publications: 19 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=0.203).
• BP6: Variant 4-78479714-C-T is Benign according to our data. Variant chr4-78479714-C-T is described in ClinVar as Benign. ClinVar VariationId is 261815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.37 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.402 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.8439C>T	p.Asp2813Asp	synonymous	Exon 56 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.8439C>T	p.Asp2813Asp	synonymous	Exon 56 of 74	ENSP00000422834.2
	FRAS1	ENST00000915768.1		c.8211C>T	p.Asp2737Asp	synonymous	Exon 55 of 73	ENSP00000585827.1
	FRAS1	ENST00000682513.1		c.8439C>T	p.Asp2813Asp	synonymous	Exon 56 of 64	ENSP00000508201.1

Frequencies

GnomAD3 genomes AF: 0.325 AC: 49456 AN: 151998 Hom.: 8789 Cov.: 33

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.388

Gnomad AMR AF: 0.410

Gnomad ASJ AF: 0.314

Gnomad EAS AF: 0.302

Gnomad SAS AF: 0.270

Gnomad FIN AF: 0.437

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.384

Gnomad OTH AF: 0.328

GnomAD2 exomes AF: 0.371 AC: 81900 AN: 220760 AF XY: 0.366

Gnomad AFR exome AF: 0.169

Gnomad AMR exome AF: 0.482

Gnomad ASJ exome AF: 0.309

Gnomad EAS exome AF: 0.315

Gnomad FIN exome AF: 0.443

Gnomad NFE exome AF: 0.390

Gnomad OTH exome AF: 0.354

GnomAD4 exome AF: 0.365 AC: 520352 AN: 1424358 Hom.: 97207 Cov.: 31 AF XY: 0.363 AC XY: 255628 AN XY: 704030

African (AFR) AF: 0.171 AC: 5630 AN: 32996

American (AMR) AF: 0.470 AC: 20032 AN: 42666

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 7291 AN: 23778

East Asian (EAS) AF: 0.305 AC: 11938 AN: 39164

South Asian (SAS) AF: 0.276 AC: 22057 AN: 79930

European-Finnish (FIN) AF: 0.443 AC: 23001 AN: 51974

Middle Eastern (MID) AF: 0.282 AC: 1544 AN: 5476

European-Non Finnish (NFE) AF: 0.375 AC: 408980 AN: 1089538

Other (OTH) AF: 0.338 AC: 19879 AN: 58836

GnomAD4 genome AF: 0.325 AC: 49496 AN: 152116 Hom.: 8800 Cov.: 33 AF XY: 0.328 AC XY: 24396 AN XY: 74356

African (AFR) AF: 0.178 AC: 7406 AN: 41526

American (AMR) AF: 0.411 AC: 6278 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.314 AC: 1089 AN: 3466

East Asian (EAS) AF: 0.302 AC: 1564 AN: 5178

South Asian (SAS) AF: 0.270 AC: 1305 AN: 4826

European-Finnish (FIN) AF: 0.437 AC: 4612 AN: 10558

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.384 AC: 26120 AN: 67966

Other (OTH) AF: 0.331 AC: 698 AN: 2110

Alfa AF: 0.350 Hom.: 6532

Bravo AF: 0.320

Asia WGS AF: 0.294 AC: 1025 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	3.1
DANN	Benign	0.21
PhyloP100		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs11098194; hg19: chr4-79400868; COSMIC: COSV53590167;