7-112462016-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001550.4(IFRD1):c.634C>G(p.Leu212Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,612,418 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (57 hom.)
• Consequence: IFRD1 NM_001550.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.48

Genes affected

IFRD1 (HGNC:5456): (interferon related developmental regulator 1) This gene is an immediate early gene that encodes a protein related to interferon-gamma. This protein may function as a transcriptional co-activator/repressor that controls the growth and differentiation of specific cell types during embryonic development and tissue regeneration. Mutations in this gene are associated with sensory/motor neuropathy with ataxia. This gene may also be involved in modulating the pathogenesis of cystic fibrosis lung disease. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Oct 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0065864623).
• BP6: Variant 7-112462016-C-G is Benign according to our data. Variant chr7-112462016-C-G is described in ClinVar as [Benign]. Clinvar id is 218480.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-112462016-C-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00177 (2591/1460266) while in subpopulation AMR AF= 0.0406 (1813/44654). AF 95% confidence interval is 0.039. There are 57 homozygotes in gnomad4_exome. There are 1111 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFRD1	NM_001550.4	c.634C>G	p.Leu212Val	missense_variant	7/12	ENST00000403825.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFRD1	ENST00000403825.8	c.634C>G	p.Leu212Val	missense_variant	7/12	1	NM_001550.4	P3

Frequencies

GnomAD3 genomes AF: 0.00258 AC: 392 AN: 152034 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0159

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00424

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00397

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00720 AC: 1805 AN: 250656 Hom.: 49 AF XY: 0.00551 AC XY: 746 AN XY: 135482

Gnomad AFR exome AF: 0.000924

Gnomad AMR exome AF: 0.0444

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00430

Gnomad SAS exome AF: 0.000850

Gnomad FIN exome AF: 0.00412

Gnomad NFE exome AF: 0.000309

Gnomad OTH exome AF: 0.00508

GnomAD4 exome AF: 0.00177 AC: 2591 AN: 1460266 Hom.: 57 Cov.: 32 AF XY: 0.00153 AC XY: 1111 AN XY: 726538

Gnomad4 AFR exome AF: 0.000449

Gnomad4 AMR exome AF: 0.0406

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00671

Gnomad4 SAS exome AF: 0.000812

Gnomad4 FIN exome AF: 0.00328

Gnomad4 NFE exome AF: 0.000129

Gnomad4 OTH exome AF: 0.00179

GnomAD4 genome AF: 0.00262 AC: 399 AN: 152152 Hom.: 9 Cov.: 32 AF XY: 0.00285 AC XY: 212 AN XY: 74384

Gnomad4 AFR AF: 0.00135

Gnomad4 AMR AF: 0.0163

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00444

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00397

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000954 Hom.: 1

Bravo AF: 0.00447

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00595 AC: 722

Asia WGS AF: 0.00462 AC: 16 AN: 3474

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 13, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	20
Dann	Uncertain	0.98
DEOGEN2	Benign	0.19	T;.;T;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.89	D
MetaRNN	Benign	0.0066	T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.2	L;.;L;.
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.84	N;.;N;N
REVEL	Benign	0.093
Sift	Benign	0.24	T;.;T;T
Sift4G	Benign	0.16	T;T;T;T
Polyphen		0.12	B;.;B;.
Vest4		0.41
MVP		0.62
MPC		0.71
ClinPred		0.013	T
GERP RS		2.8
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.089
gMVP		0.50

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: rs79480470; hg19: chr7-112102071; COSMIC: COSV50044891; COSMIC: COSV50044891;