NM_025074.7:c.9116-6C>T

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: 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=-0.8).
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRAS1	NM_025074.7	c.9116-6C>T		splice_region_variant, intron_variant	Intron 60 of 73	ENST00000512123.4	NP_079350.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRAS1	ENST00000512123.4	c.9116-6C>T		splice_region_variant, intron_variant	Intron 60 of 73	5	NM_025074.7	ENSP00000422834.2
FRAS1	ENST00000682513.1	c.9116-6C>T		splice_region_variant, intron_variant	Intron 60 of 63			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

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fraser syndrome 1 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

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;