rs778075842

Variant names:

• chr15-30905765-C-T
• rs778075842
• NM_014967.5:c.1102C>T

Your query was ambiguous. Multiple possible variants found:

• chr15-30905765-C-T
• chr15-30905765-C-G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_014967.5(FAN1):​c.1102C>T​(p.Gln368*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FAN1 NM_014967.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.267
• Publications: 0 publications found

Genes affected

FAN1 (HGNC:29170): (FANCD2 and FANCI associated nuclease 1) This gene plays a role in DNA interstrand cross-link repair and encodes a protein with 5' flap endonuclease and 5'-3' exonuclease activity. Mutations in this gene cause karyomegalic interstitial nephritis. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Feb 2016]

FAN1 Gene-Disease associations (from GenCC):

• karyomegalic interstitial nephritis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Lynch syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: Unknown Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-30905765-C-T is Pathogenic according to our data. Variant chr15-30905765-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 437428.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014967.5. 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
	FAN1	NM_014967.5	MANE Select	c.1102C>T	p.Gln368*	stop_gained	Exon 2 of 15	NP_055782.3	Q9Y2M0-1
	FAN1	NM_001146094.2		c.1102C>T	p.Gln368*	stop_gained	Exon 2 of 4	NP_001139566.1	Q9Y2M0-2
	FAN1	NM_001146095.1		c.1102C>T	p.Gln368*	stop_gained	Exon 2 of 4	NP_001139567.1	Q9Y2M0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAN1	ENST00000362065.9	TSL:1 MANE Select	c.1102C>T	p.Gln368*	stop_gained	Exon 2 of 15	ENSP00000354497.4	Q9Y2M0-1
	FAN1	ENST00000561594.5	TSL:1	c.1102C>T	p.Gln368*	stop_gained	Exon 2 of 4	ENSP00000455983.1	Q9Y2M0-2
	FAN1	ENST00000561607.6	TSL:1	c.1102C>T	p.Gln368*	stop_gained	Exon 2 of 4	ENSP00000454223.1	Q9Y2M0-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Karyomegalic interstitial nephritis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	27
DANN	Benign	0.95
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.21	N
PhyloP100		-0.27
Vest4		0.32
GERP RS		-5.4
Mutation Taster		=2/198	disease causing (ClinVar)

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: rs778075842; hg19: chr15-31197968;