NM_025074.7:c.-257G>T

Variant names:

• chr4-78057753-G-T
• rs78363185
• NM_025074.7:c.-257G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_025074.7(FRAS1):​c.-257G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00523 in 544,834 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (49 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (14 hom.)
• Consequence: FRAS1 NM_025074.7 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.222
• 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=-0.56).
• BP6: Variant 4-78057753-G-T is Benign according to our data. Variant chr4-78057753-G-T is described in ClinVar as Benign. ClinVar VariationId is 349644.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0137 (2088/152314) while in subpopulation AFR AF = 0.0476 (1981/41576). AF 95% confidence interval is 0.0459. There are 49 homozygotes in GnomAd4. There are 1021 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 49 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.-257G>T		5_prime_UTR	Exon 1 of 74	NP_079350.5
	FRAS1	NM_001166133.2		c.-257G>T		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.-257G>T		5_prime_UTR	Exon 1 of 74	ENSP00000422834.2	Q86XX4-2
	FRAS1	ENST00000325942.11	TSL:1	c.-257G>T		5_prime_UTR	Exon 1 of 42	ENSP00000326330.6	Q86XX4-5
	FRAS1	ENST00000508900.2	TSL:1	c.-257G>T		5_prime_UTR	Exon 1 of 20	ENSP00000423809.2	Q86XX4-6

Frequencies

GnomAD3 genomes AF: 0.0137 AC: 2088 AN: 152196 Hom.: 49 Cov.: 32

Gnomad AFR AF: 0.0478

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00543

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00718

GnomAD4 exome AF: 0.00194 AC: 763 AN: 392520 Hom.: 14 Cov.: 0 AF XY: 0.00164 AC XY: 333 AN XY: 202908

African (AFR) AF: 0.0506 AC: 574 AN: 11350

American (AMR) AF: 0.00279 AC: 47 AN: 16876

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12438

East Asian (EAS) AF: 0.000586 AC: 17 AN: 28990

South Asian (SAS) AF: 0.0000967 AC: 3 AN: 31036

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27888

Middle Eastern (MID) AF: 0.00346 AC: 6 AN: 1736

European-Non Finnish (NFE) AF: 0.000117 AC: 28 AN: 238522

Other (OTH) AF: 0.00372 AC: 88 AN: 23684

GnomAD4 genome AF: 0.0137 AC: 2088 AN: 152314 Hom.: 49 Cov.: 32 AF XY: 0.0137 AC XY: 1021 AN XY: 74486

African (AFR) AF: 0.0476 AC: 1981 AN: 41576

American (AMR) AF: 0.00536 AC: 82 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5162

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68030

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.0241 Hom.: 21

Bravo AF: 0.0157

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Fraser syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	8.8
DANN	Benign	0.95
PhyloP100		0.22
PromoterAI		-0.044	Neutral
Mutation Taster		=293/7	polymorphism

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: rs78363185; hg19: chr4-78978907;