4-78464565-G-T

Variant names:

• chr4-78464565-G-T
• NM_025074.7:c.7011G>T
• FRAS1 p.Ala2337Ala

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_025074.7(FRAS1):​c.7011G>T​(p.Ala2337Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. A2337A) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: FRAS1 NM_025074.7 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.52
• Publications: 0 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: Labcorp Genetics (formerly Invitae), G2P
• renal agenesis, unilateral

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (REVEL=0.031).
• BP6: Variant 4-78464565-G-T is Benign according to our data. Variant chr4-78464565-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3643571.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.53 with no splicing effect.

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.7011G>T	p.Ala2337Ala	synonymous	Exon 49 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.7011G>T	p.Ala2337Ala	synonymous	Exon 49 of 74	ENSP00000422834.2	Q86XX4-2
	FRAS1	ENST00000915768.1		c.7011G>T	p.Ala2337Ala	synonymous	Exon 49 of 73	ENSP00000585827.1
	FRAS1	ENST00000682513.1		c.7011G>T	p.Ala2337Ala	synonymous	Exon 49 of 64	ENSP00000508201.1	A0A804HL50

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 41

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.038
DANN	Benign	0.65
PhyloP100		-2.5

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr4-79385719;