4-78438731-T-G

Variant names:

• chr4-78438731-T-G
• rs2170899
• NM_025074.7:c.5366+13T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_025074.7(FRAS1):​c.5366+13T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.36 in 1,566,774 control chromosomes in the GnomAD database, including 105,191 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8434 hom., cov: 33)
  • Exomes 𝑓: 0.37 (96757 hom.)
• Consequence: FRAS1 NM_025074.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.643
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 4-78438731-T-G is Benign according to our data. Variant chr4-78438731-T-G is described in ClinVar as Benign. ClinVar VariationId is 197083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.393 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.5366+13T>G		intron	N/A	NP_079350.5
	FRAS1	NM_001166133.2		c.5366+13T>G		intron	N/A	NP_001159605.1	Q86XX4-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRAS1	ENST00000512123.4	TSL:5 MANE Select	c.5366+13T>G		intron	N/A	ENSP00000422834.2	Q86XX4-2
	FRAS1	ENST00000325942.11	TSL:1	c.5366+13T>G		intron	N/A	ENSP00000326330.6	Q86XX4-5
	FRAS1	ENST00000915768.1		c.5366+13T>G		intron	N/A	ENSP00000585827.1

Frequencies

GnomAD3 genomes AF: 0.312 AC: 47385 AN: 151978 Hom.: 8424 Cov.: 33

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.378

Gnomad AMR AF: 0.401

Gnomad ASJ AF: 0.332

Gnomad EAS AF: 0.288

Gnomad SAS AF: 0.303

Gnomad FIN AF: 0.436

Gnomad MID AF: 0.248

Gnomad NFE AF: 0.383

Gnomad OTH AF: 0.315

GnomAD2 exomes AF: 0.376 AC: 71380 AN: 190090 AF XY: 0.372

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.479

Gnomad ASJ exome AF: 0.332

Gnomad EAS exome AF: 0.313

Gnomad FIN exome AF: 0.447

Gnomad NFE exome AF: 0.396

Gnomad OTH exome AF: 0.356

GnomAD4 exome AF: 0.365 AC: 517044 AN: 1414678 Hom.: 96757 Cov.: 28 AF XY: 0.365 AC XY: 255509 AN XY: 700788

African (AFR) AF: 0.120 AC: 3820 AN: 31866

American (AMR) AF: 0.462 AC: 16576 AN: 35896

Ashkenazi Jewish (ASJ) AF: 0.330 AC: 8369 AN: 25336

East Asian (EAS) AF: 0.302 AC: 11661 AN: 38600

South Asian (SAS) AF: 0.306 AC: 24548 AN: 80162

European-Finnish (FIN) AF: 0.445 AC: 23026 AN: 51770

Middle Eastern (MID) AF: 0.276 AC: 1569 AN: 5684

European-Non Finnish (NFE) AF: 0.375 AC: 407704 AN: 1086556

Other (OTH) AF: 0.336 AC: 19771 AN: 58808

GnomAD4 genome AF: 0.312 AC: 47413 AN: 152096 Hom.: 8434 Cov.: 33 AF XY: 0.315 AC XY: 23388 AN XY: 74340

African (AFR) AF: 0.132 AC: 5472 AN: 41526

American (AMR) AF: 0.402 AC: 6140 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.332 AC: 1151 AN: 3468

East Asian (EAS) AF: 0.289 AC: 1494 AN: 5176

South Asian (SAS) AF: 0.302 AC: 1459 AN: 4824

European-Finnish (FIN) AF: 0.436 AC: 4597 AN: 10546

Middle Eastern (MID) AF: 0.243 AC: 71 AN: 292

European-Non Finnish (NFE) AF: 0.383 AC: 26018 AN: 67964

Other (OTH) AF: 0.317 AC: 666 AN: 2104

Alfa AF: 0.349 Hom.: 12450

Bravo AF: 0.304

Asia WGS AF: 0.291 AC: 1013 AN: 3478

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	-0.82
CADD	Benign	7.7
DANN	Benign	0.49
PhyloP100		0.64
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: rs2170899; hg19: chr4-79359885; COSMIC: COSV53590107;