4-78057987-C-T

Variant names:

• chr4-78057987-C-T
• rs34237418
• NM_025074.7:c.-23C>T

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.-23C>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 0.187 in 1,611,780 control chromosomes in the GnomAD database, including 30,439 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2236 hom., cov: 32)
  • Exomes 𝑓: 0.19 (28203 hom.)
• Consequence: FRAS1 NM_025074.7 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.707
• 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=-0.53).
• BP6: Variant 4-78057987-C-T is Benign according to our data. Variant chr4-78057987-C-T is described in ClinVar as Benign. ClinVar VariationId is 349649.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.203 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.-23C>T		5_prime_UTR	Exon 1 of 74	NP_079350.5
	FRAS1	NM_001166133.2		c.-23C>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.-23C>T		5_prime_UTR	Exon 1 of 74	ENSP00000422834.2	Q86XX4-2
	FRAS1	ENST00000325942.11	TSL:1	c.-23C>T		5_prime_UTR	Exon 1 of 42	ENSP00000326330.6	Q86XX4-5
	FRAS1	ENST00000508900.2	TSL:1	c.-23C>T		5_prime_UTR	Exon 1 of 20	ENSP00000423809.2	Q86XX4-6

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23376 AN: 152124 Hom.: 2236 Cov.: 32

Gnomad AFR AF: 0.0578

Gnomad AMI AF: 0.328

Gnomad AMR AF: 0.195

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.0183

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.210

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.206

Gnomad OTH AF: 0.155

GnomAD2 exomes AF: 0.164 AC: 40598 AN: 248250 AF XY: 0.162

Gnomad AFR exome AF: 0.0518

Gnomad AMR exome AF: 0.185

Gnomad ASJ exome AF: 0.152

Gnomad EAS exome AF: 0.0188

Gnomad FIN exome AF: 0.208

Gnomad NFE exome AF: 0.204

Gnomad OTH exome AF: 0.174

GnomAD4 exome AF: 0.190 AC: 277407 AN: 1459538 Hom.: 28203 Cov.: 31 AF XY: 0.187 AC XY: 135962 AN XY: 726100

African (AFR) AF: 0.0532 AC: 1780 AN: 33440

American (AMR) AF: 0.185 AC: 8264 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 3940 AN: 26098

East Asian (EAS) AF: 0.0194 AC: 770 AN: 39686

South Asian (SAS) AF: 0.101 AC: 8707 AN: 86176

European-Finnish (FIN) AF: 0.203 AC: 10808 AN: 53274

Middle Eastern (MID) AF: 0.156 AC: 896 AN: 5762

European-Non Finnish (NFE) AF: 0.209 AC: 231599 AN: 1110142

Other (OTH) AF: 0.176 AC: 10643 AN: 60302

GnomAD4 genome AF: 0.154 AC: 23376 AN: 152242 Hom.: 2236 Cov.: 32 AF XY: 0.151 AC XY: 11230 AN XY: 74440

African (AFR) AF: 0.0577 AC: 2398 AN: 41564

American (AMR) AF: 0.195 AC: 2982 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 527 AN: 3470

East Asian (EAS) AF: 0.0184 AC: 95 AN: 5176

South Asian (SAS) AF: 0.104 AC: 502 AN: 4826

European-Finnish (FIN) AF: 0.210 AC: 2226 AN: 10594

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.206 AC: 13977 AN: 67992

Other (OTH) AF: 0.154 AC: 325 AN: 2110

Alfa AF: 0.193 Hom.: 4074

Bravo AF: 0.149

Asia WGS AF: 0.0770 AC: 270 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	-0.53
CADD	Benign	8.4
DANN	Uncertain	0.98
PhyloP100		-0.71
PromoterAI		-0.075	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Mutation Taster		=287/13	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: rs34237418; hg19: chr4-78979141; COSMIC: COSV53603985;