11-299391-G-T

Variant names:

• chr11-299391-G-T
• rs531009160
• NM_001025295.3:c.100C>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001025295.3(IFITM5):​c.100C>A​(p.Arg34Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,425,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: IFITM5 NM_001025295.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.40
• Publications: 0 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP7: Synonymous conserved (PhyloP=1.4 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFITM5	NM_001025295.3	c.100C>A	p.Arg34Arg	synonymous_variant	Exon 1 of 2	ENST00000382614.2	NP_001020466.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFITM5	ENST00000382614.2	c.100C>A	p.Arg34Arg	synonymous_variant	Exon 1 of 2	1	NM_001025295.3	ENSP00000372059.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.01e-7 AC: 1 AN: 1425618 Hom.: 0 Cov.: 33 AF XY: 0.00000141 AC XY: 1 AN XY: 706850

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32028

American (AMR) AF: 0.00 AC: 0 AN: 39610

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25156

East Asian (EAS) AF: 0.00 AC: 0 AN: 37162

South Asian (SAS) AF: 0.00 AC: 0 AN: 81496

European-Finnish (FIN) AF: 0.0000199 AC: 1 AN: 50184

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1095324

Other (OTH) AF: 0.00 AC: 0 AN: 58958

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.4
DANN	Benign	0.73
PhyloP100		1.4
PromoterAI		-0.021	Neutral

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: rs531009160; hg19: chr11-299391;