4-78516024-C-T

Variant names:

• chr4-78516024-C-T
• rs74632598
• NM_025074.7:c.10389+11C>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.10389+11C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 1,604,770 control chromosomes in the GnomAD database, including 29,319 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1784 hom., cov: 32)
  • Exomes 𝑓: 0.18 (27535 hom.)
• Consequence: FRAS1 NM_025074.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.728
• Publications: 5 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=-0.84).
• BP6: Variant 4-78516024-C-T is Benign according to our data. Variant chr4-78516024-C-T is described in ClinVar as Benign. ClinVar VariationId is 261796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.197 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.10389+11C>T		intron	N/A	NP_079350.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRAS1	ENST00000512123.4	TSL:5 MANE Select	c.10389+11C>T		intron	N/A	ENSP00000422834.2
	FRAS1	ENST00000915768.1		c.10161+11C>T		intron	N/A	ENSP00000585827.1

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21245 AN: 152028 Hom.: 1784 Cov.: 32

Gnomad AFR AF: 0.0783

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.00289

Gnomad SAS AF: 0.0535

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.133

GnomAD2 exomes AF: 0.138 AC: 32581 AN: 236748 AF XY: 0.137

Gnomad AFR exome AF: 0.0757

Gnomad AMR exome AF: 0.0782

Gnomad ASJ exome AF: 0.117

Gnomad EAS exome AF: 0.00171

Gnomad FIN exome AF: 0.155

Gnomad NFE exome AF: 0.206

Gnomad OTH exome AF: 0.155

GnomAD4 exome AF: 0.185 AC: 268299 AN: 1452624 Hom.: 27535 Cov.: 30 AF XY: 0.181 AC XY: 130459 AN XY: 722146

African (AFR) AF: 0.0745 AC: 2477 AN: 33264

American (AMR) AF: 0.0827 AC: 3604 AN: 43600

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 2950 AN: 25938

East Asian (EAS) AF: 0.00208 AC: 82 AN: 39392

South Asian (SAS) AF: 0.0586 AC: 4998 AN: 85226

European-Finnish (FIN) AF: 0.156 AC: 8263 AN: 53092

Middle Eastern (MID) AF: 0.0947 AC: 543 AN: 5732

European-Non Finnish (NFE) AF: 0.213 AC: 235679 AN: 1106310

Other (OTH) AF: 0.162 AC: 9703 AN: 60070

GnomAD4 genome AF: 0.140 AC: 21245 AN: 152146 Hom.: 1784 Cov.: 32 AF XY: 0.135 AC XY: 10015 AN XY: 74388

African (AFR) AF: 0.0781 AC: 3243 AN: 41506

American (AMR) AF: 0.116 AC: 1778 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 385 AN: 3470

East Asian (EAS) AF: 0.00289 AC: 15 AN: 5186

South Asian (SAS) AF: 0.0533 AC: 256 AN: 4802

European-Finnish (FIN) AF: 0.147 AC: 1558 AN: 10586

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.200 AC: 13585 AN: 67994

Other (OTH) AF: 0.132 AC: 279 AN: 2114

Alfa AF: 0.132 Hom.: 512

Bravo AF: 0.135

Asia WGS AF: 0.0360 AC: 126 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.2
DANN	Benign	0.49
PhyloP100		-0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs74632598; hg19: chr4-79437178;