11-298542-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001025295.3(IFITM5):c.358G>A(p.Ala120Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000843 in 1,612,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000081 (0 hom.)
• Consequence: IFITM5 NM_001025295.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.19

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.084510356).
• BP6: Variant 11-298542-C-T is Benign according to our data. Variant chr11-298542-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2069253.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
• BS2: High AC in GnomAd at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFITM5	NM_001025295.3	c.358G>A	p.Ala120Thr	missense_variant	2/2	ENST00000382614.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFITM5	ENST00000382614.2	c.358G>A	p.Ala120Thr	missense_variant	2/2	1	NM_001025295.3	P1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000882 AC: 22 AN: 249482 Hom.: 0 AF XY: 0.0000665 AC XY: 9 AN XY: 135380

Gnomad AFR exome AF: 0.0000624

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000116

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000808 AC: 118 AN: 1460322 Hom.: 0 Cov.: 31 AF XY: 0.0000661 AC XY: 48 AN XY: 726466

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000872

Gnomad4 OTH exome AF: 0.0000829

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152236 Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7 AN XY: 74366

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000207 Hom.: 0

Bravo AF: 0.000121

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 04, 2022

The c.358G>A (p.A120T) alteration is located in exon 2 (coding exon 2) of the IFITM5 gene. This alteration results from a G to A substitution at nucleotide position 358, causing the alanine (A) at amino acid position 120 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	16
Dann	Benign	0.97
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.46
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.61	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.085	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	0.87	N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.094
Sift	Benign	0.43	T
Sift4G	Benign	0.28	T
Polyphen		0.14	B
Vest4		0.060
MVP		0.51
MPC		0.012
ClinPred		0.025	T
GERP RS		1.6
Varity_R		0.034
gMVP		0.19

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

Publications

LitVar

Other links and lift over

dbSNP: rs150598773; hg19: chr11-298542;