rs76630865

Variant names:

• chr4-78499715-C-T
• rs76630865
• NM_025074.7:c.9116-6C>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.9116-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 1,611,622 control chromosomes in the GnomAD database, including 25,504 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2557 hom., cov: 33)
  • Exomes 𝑓: 0.18 (22947 hom.)
• Consequence: FRAS1 NM_025074.7 splice_region, intron
• Scores: Splicing: ADA: 0.00006390
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0530
• 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: Labcorp Genetics (formerly Invitae), G2P
• 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=-0.8).
• BP6: Variant 4-78499715-C-T is Benign according to our data. Variant chr4-78499715-C-T is described in ClinVar as Benign. ClinVar VariationId is 261819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.208 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.9116-6C>T		splice_region 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.9116-6C>T		splice_region intron	N/A	ENSP00000422834.2
	FRAS1	ENST00000915768.1		c.8888-6C>T		splice_region intron	N/A	ENSP00000585827.1
	FRAS1	ENST00000682513.1		c.9116-6C>T		splice_region intron	N/A	ENSP00000508201.1

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27515 AN: 152030 Hom.: 2557 Cov.: 33

Gnomad AFR AF: 0.174

Gnomad AMI AF: 0.132

Gnomad AMR AF: 0.169

Gnomad ASJ AF: 0.257

Gnomad EAS AF: 0.218

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.200

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.181

Gnomad OTH AF: 0.189

GnomAD2 exomes AF: 0.177 AC: 44060 AN: 248434 AF XY: 0.176

Gnomad AFR exome AF: 0.171

Gnomad AMR exome AF: 0.137

Gnomad ASJ exome AF: 0.255

Gnomad EAS exome AF: 0.222

Gnomad FIN exome AF: 0.199

Gnomad NFE exome AF: 0.182

Gnomad OTH exome AF: 0.172

GnomAD4 exome AF: 0.176 AC: 256763 AN: 1459474 Hom.: 22947 Cov.: 32 AF XY: 0.175 AC XY: 127095 AN XY: 726050

African (AFR) AF: 0.178 AC: 5967 AN: 33438

American (AMR) AF: 0.143 AC: 6402 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 6548 AN: 26094

East Asian (EAS) AF: 0.205 AC: 8147 AN: 39670

South Asian (SAS) AF: 0.144 AC: 12367 AN: 86054

European-Finnish (FIN) AF: 0.205 AC: 10938 AN: 53362

Middle Eastern (MID) AF: 0.220 AC: 1211 AN: 5510

European-Non Finnish (NFE) AF: 0.175 AC: 193914 AN: 1110412

Other (OTH) AF: 0.187 AC: 11269 AN: 60266

GnomAD4 genome AF: 0.181 AC: 27520 AN: 152148 Hom.: 2557 Cov.: 33 AF XY: 0.182 AC XY: 13528 AN XY: 74378

African (AFR) AF: 0.174 AC: 7216 AN: 41510

American (AMR) AF: 0.169 AC: 2581 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.257 AC: 893 AN: 3470

East Asian (EAS) AF: 0.218 AC: 1129 AN: 5174

South Asian (SAS) AF: 0.140 AC: 676 AN: 4820

European-Finnish (FIN) AF: 0.200 AC: 2110 AN: 10574

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.181 AC: 12324 AN: 67996

Other (OTH) AF: 0.187 AC: 395 AN: 2110

Alfa AF: 0.185 Hom.: 1175

Bravo AF: 0.179

Asia WGS AF: 0.201 AC: 700 AN: 3478

EpiCase AF: 0.184

EpiControl AF: 0.187

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	-0.80
CADD	Benign	2.2
DANN	Benign	0.53
PhyloP100		0.053
Mutation Taster		=89/11	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000064
dbscSNV1_RF	Benign	0.0020
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: rs76630865; hg19: chr4-79420869;