rs3740615

Variant names:

• chr11-22625820-G-A
• rs3740615
• NM_022725.4:c.-10C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-22625820-G-A
• chr11-22625820-G-C
• chr11-22625820-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022725.4(FANCF):​c.-10C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.174 in 1,613,436 control chromosomes in the GnomAD database, including 26,539 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2058 hom., cov: 32)
  • Exomes 𝑓: 0.18 (24481 hom.)
• Consequence: FANCF NM_022725.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -4.17
• Publications: 30 publications found

Genes affected

FANCF (HGNC:3587): (FA complementation group F) The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group F. [provided by RefSeq, Jul 2008]

GAS2 (HGNC:4167): (growth arrest specific 2) The protein encoded by this gene is a caspase-3 substrate that plays a role in regulating microfilament and cell shape changes during apoptosis. It can also modulate cell susceptibility to p53-dependent apoptosis by inhibiting calpain activity. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2017]

GAS2 Gene-Disease associations (from GenCC):

• hearing loss disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hearing loss, autosomal recessive 125

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 11-22625820-G-A is Benign according to our data. Variant chr11-22625820-G-A is described in CliVar as Benign. Clinvar id is 261630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-22625820-G-A is described in CliVar as Benign. Clinvar id is 261630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-22625820-G-A is described in CliVar as Benign. Clinvar id is 261630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.206 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCF	NM_022725.4	c.-10C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 1	ENST00000327470.6	NP_073562.1
FANCF	NM_022725.4	c.-10C>T		5_prime_UTR_variant	Exon 1 of 1	ENST00000327470.6	NP_073562.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCF	ENST00000327470.6	c.-10C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 1	6	NM_022725.4	ENSP00000330875.3
FANCF	ENST00000327470.6	c.-10C>T		5_prime_UTR_variant	Exon 1 of 1	6	NM_022725.4	ENSP00000330875.3
GAS2	ENST00000648096.1	n.312G>A		non_coding_transcript_exon_variant	Exon 1 of 1
GAS2	ENST00000528582.5	c.-21+7G>A		splice_region_variant, intron_variant	Intron 1 of 5	3		ENSP00000432584.1

Frequencies

GnomAD3 genomes AF: 0.148 AC: 22573 AN: 152020 Hom.: 2057 Cov.: 32

Gnomad AFR AF: 0.0610

Gnomad AMI AF: 0.121

Gnomad AMR AF: 0.0980

Gnomad ASJ AF: 0.197

Gnomad EAS AF: 0.216

Gnomad SAS AF: 0.0671

Gnomad FIN AF: 0.293

Gnomad MID AF: 0.162

Gnomad NFE AF: 0.189

Gnomad OTH AF: 0.153

GnomAD2 exomes AF: 0.158 AC: 39234 AN: 248564 AF XY: 0.159

Gnomad AFR exome AF: 0.0605

Gnomad AMR exome AF: 0.0758

Gnomad ASJ exome AF: 0.193

Gnomad EAS exome AF: 0.218

Gnomad FIN exome AF: 0.294

Gnomad NFE exome AF: 0.182

Gnomad OTH exome AF: 0.170

GnomAD4 exome AF: 0.177 AC: 257950 AN: 1461298 Hom.: 24481 Cov.: 34 AF XY: 0.174 AC XY: 126318 AN XY: 726926

African (AFR) AF: 0.0561 AC: 1878 AN: 33478

American (AMR) AF: 0.0789 AC: 3529 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.196 AC: 5120 AN: 26136

East Asian (EAS) AF: 0.203 AC: 8074 AN: 39694

South Asian (SAS) AF: 0.0699 AC: 6030 AN: 86232

European-Finnish (FIN) AF: 0.288 AC: 15372 AN: 53350

Middle Eastern (MID) AF: 0.177 AC: 984 AN: 5550

European-Non Finnish (NFE) AF: 0.186 AC: 206911 AN: 1111780

Other (OTH) AF: 0.167 AC: 10052 AN: 60364

GnomAD4 genome AF: 0.148 AC: 22580 AN: 152138 Hom.: 2058 Cov.: 32 AF XY: 0.151 AC XY: 11233 AN XY: 74354

African (AFR) AF: 0.0610 AC: 2532 AN: 41530

American (AMR) AF: 0.0978 AC: 1495 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.197 AC: 685 AN: 3472

East Asian (EAS) AF: 0.217 AC: 1119 AN: 5160

South Asian (SAS) AF: 0.0665 AC: 321 AN: 4824

European-Finnish (FIN) AF: 0.293 AC: 3095 AN: 10552

Middle Eastern (MID) AF: 0.168 AC: 49 AN: 292

European-Non Finnish (NFE) AF: 0.189 AC: 12847 AN: 67990

Other (OTH) AF: 0.155 AC: 327 AN: 2114

Alfa AF: 0.161 Hom.: 6507

Bravo AF: 0.132

Asia WGS AF: 0.140 AC: 488 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group F Benign:4

Jan 13, 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. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 06, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Jan 10, 2019

GeneDx

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

- -

Fanconi anemia Benign:1

Nov 22, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.0070
DANN	Benign	0.84
PhyloP100		-4.2
PromoterAI		-0.057	Neutral
Mutation Taster		=299/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs3740615; hg19: chr11-22647366; COSMIC: COSV59416462;