NM_025074.7:c.4095C>T

Variant names:

• chr4-78400853-C-T
• rs79869130
• NM_025074.7:c.4095C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_025074.7(FRAS1):​c.4095C>T​(p.Ile1365Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000568 in 1,613,694 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00083 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00054 (4 hom.)
• Consequence: FRAS1 NM_025074.7 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 0.171
• 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: G2P, Labcorp Genetics (formerly Invitae)
• renal agenesis, unilateral

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 4-78400853-C-T is Benign according to our data. Variant chr4-78400853-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 435257.
• BP7: Synonymous conserved (PhyloP=0.171 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000834 (127/152266) while in subpopulation NFE AF = 0.00156 (106/68020). AF 95% confidence interval is 0.00132. There are 0 homozygotes in GnomAd4. There are 60 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR,AD gene

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.4095C>T	p.Ile1365Ile	synonymous	Exon 30 of 74	NP_079350.5
	FRAS1	NM_001166133.2		c.4095C>T	p.Ile1365Ile	synonymous	Exon 30 of 42	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.4095C>T	p.Ile1365Ile	synonymous	Exon 30 of 74	ENSP00000422834.2	Q86XX4-2
	FRAS1	ENST00000325942.11	TSL:1	c.4095C>T	p.Ile1365Ile	synonymous	Exon 30 of 42	ENSP00000326330.6	Q86XX4-5
	FRAS1	ENST00000915768.1		c.4095C>T	p.Ile1365Ile	synonymous	Exon 30 of 73	ENSP00000585827.1

Frequencies

GnomAD3 genomes AF: 0.000835 AC: 127 AN: 152148 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000639 AC: 159 AN: 248754 AF XY: 0.000660

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00116

Gnomad NFE exome AF: 0.000984

Gnomad OTH exome AF: 0.000828

GnomAD4 exome AF: 0.000541 AC: 790 AN: 1461428 Hom.: 4 Cov.: 31 AF XY: 0.000583 AC XY: 424 AN XY: 726972

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00211 AC: 55 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86190

European-Finnish (FIN) AF: 0.00125 AC: 67 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000572 AC: 636 AN: 1111728

Other (OTH) AF: 0.000530 AC: 32 AN: 60368

GnomAD4 genome AF: 0.000834 AC: 127 AN: 152266 Hom.: 0 Cov.: 33 AF XY: 0.000806 AC XY: 60 AN XY: 74450

African (AFR) AF: 0.0000241 AC: 1 AN: 41546

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00156 AC: 106 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00145 Hom.: 0

Bravo AF: 0.000450

EpiCase AF: 0.000818

EpiControl AF: 0.000297

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	5.9
DANN	Benign	0.69
PhyloP100		0.17
Mutation Taster		=100/0	polymorphism

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: rs79869130; hg19: chr4-79322007;