rs786201032

Variant names:

• chr11-299372-G-A
• rs786201032
• NM_001025295.3:c.119C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-299372-G-A
• chr11-299372-G-C
• chr11-299372-G-T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001025295.3(IFITM5):​c.119C>T​(p.Ser40Leu) variant causes a missense change involving the alteration of a 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S40W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: IFITM5 NM_001025295.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 8.20
• Publications: 36 publications found

Genes affected

IFITM5 (HGNC:16644): (interferon induced transmembrane protein 5) This gene encodes a membrane protein thought to play a role in bone mineralization. This gene is located on chromosome 11 in a cluster of related genes which are induced by interferon, however, this gene has not been shown to be interferon inducible. A similar gene, located in a gene cluster on mouse chromosome 7, is a member of the interferon-inducible fragilis gene family. The mouse gene encodes a transmembrane protein described as participating in germ cell competence. A mutation in the 5' UTR of this gene has been associated with osteogenesis imperfecta type V (PMID: 22863190, 22863195). [provided by RefSeq, Aug 2012]

IFITM5 Gene-Disease associations (from GenCC):

• osteogenesis imperfecta type 5

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-299372-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 689498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 11-299372-G-A is Pathogenic according to our data. Variant chr11-299372-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 183677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001025295.3. 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
	IFITM5	NM_001025295.3	MANE Select	c.119C>T	p.Ser40Leu	missense	Exon 1 of 2	NP_001020466.1	A6NNB3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFITM5	ENST00000382614.2	TSL:1 MANE Select	c.119C>T	p.Ser40Leu	missense	Exon 1 of 2	ENSP00000372059.2	A6NNB3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1443964 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 717030

African (AFR) AF: 0.00 AC: 0 AN: 32702

American (AMR) AF: 0.00 AC: 0 AN: 42694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25684

East Asian (EAS) AF: 0.00 AC: 0 AN: 38394

South Asian (SAS) AF: 0.00 AC: 0 AN: 83580

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51440

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1104104

Other (OTH) AF: 0.00 AC: 0 AN: 59632

GnomAD4 genome Cov.: 31

Alfa AF: 0.00167 Hom.: 2

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Osteogenesis imperfecta type 5 (5)
2	-	-	not provided (2)
1	-	-	IFITM5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		8.2
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.82		Loss of catalytic residue at S40 (P = 0.0077)
MVP		0.83
MPC		0.082
ClinPred		1.0	D
GERP RS		4.2
PromoterAI		-0.0017	Neutral
Varity_R		0.96
gMVP		0.92
Mutation Taster		=10/90	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs786201032; hg19: chr11-299372;