NM_025074.7:c.-65T>C

Variant names:

• chr4-78057945-T-C
• rs6832285
• NM_025074.7:c.-65T>C

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.-65T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0256 in 1,524,990 control chromosomes in the GnomAD database, including 3,694 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.088 (1609 hom., cov: 32)
  • Exomes 𝑓: 0.019 (2085 hom.)
• Consequence: FRAS1 NM_025074.7 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.257
• Publications: 3 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=-0.58).
• BP6: Variant 4-78057945-T-C is Benign according to our data. Variant chr4-78057945-T-C is described in ClinVar as Benign. ClinVar VariationId is 349648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.264 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.-65T>C		5_prime_UTR	Exon 1 of 74	NP_079350.5
	FRAS1	NM_001166133.2		c.-65T>C		5_prime_UTR	Exon 1 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.-65T>C		5_prime_UTR	Exon 1 of 74	ENSP00000422834.2	Q86XX4-2
	FRAS1	ENST00000325942.11	TSL:1	c.-65T>C		5_prime_UTR	Exon 1 of 42	ENSP00000326330.6	Q86XX4-5
	FRAS1	ENST00000508900.2	TSL:1	c.-65T>C		5_prime_UTR	Exon 1 of 20	ENSP00000423809.2	Q86XX4-6

Frequencies

GnomAD3 genomes AF: 0.0873 AC: 13283 AN: 152082 Hom.: 1598 Cov.: 32

Gnomad AFR AF: 0.268

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0504

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.129

Gnomad SAS AF: 0.101

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00147

Gnomad OTH AF: 0.0641

GnomAD4 exome AF: 0.0187 AC: 25711 AN: 1372790 Hom.: 2085 Cov.: 20 AF XY: 0.0199 AC XY: 13668 AN XY: 685732

African (AFR) AF: 0.272 AC: 8586 AN: 31566

American (AMR) AF: 0.0434 AC: 1880 AN: 43360

Ashkenazi Jewish (ASJ) AF: 0.00321 AC: 80 AN: 24948

East Asian (EAS) AF: 0.132 AC: 5165 AN: 39068

South Asian (SAS) AF: 0.0849 AC: 7070 AN: 83242

European-Finnish (FIN) AF: 0.000495 AC: 26 AN: 52554

Middle Eastern (MID) AF: 0.0182 AC: 101 AN: 5546

European-Non Finnish (NFE) AF: 0.000855 AC: 885 AN: 1035162

Other (OTH) AF: 0.0334 AC: 1918 AN: 57344

GnomAD4 genome AF: 0.0877 AC: 13343 AN: 152200 Hom.: 1609 Cov.: 32 AF XY: 0.0878 AC XY: 6533 AN XY: 74440

African (AFR) AF: 0.269 AC: 11157 AN: 41536

American (AMR) AF: 0.0505 AC: 772 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3464

East Asian (EAS) AF: 0.130 AC: 669 AN: 5162

South Asian (SAS) AF: 0.101 AC: 486 AN: 4826

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10612

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00147 AC: 100 AN: 67990

Other (OTH) AF: 0.0644 AC: 136 AN: 2112

Alfa AF: 0.0387 Hom.: 374

Bravo AF: 0.0967

Asia WGS AF: 0.126 AC: 437 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	16
DANN	Benign	0.83
PhyloP100		0.26
PromoterAI		-0.073	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=284/16	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: rs6832285; hg19: chr4-78979099;