Genetic Variant CD74:p.Arg46Leu (chr5-150407313-C-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001025159.3(CD74):c.137G>T(p.Arg46Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000056 in 1,607,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

CD74
NM_001025159.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.13

Variant links:

Genes affected

CD74 (HGNC:1697): (CD74 molecule) The protein encoded by this gene associates with class II major histocompatibility complex (MHC) and is an important chaperone that regulates antigen presentation for immune response. It also serves as cell surface receptor for the cytokine macrophage migration inhibitory factor (MIF) which, when bound to the encoded protein, initiates survival pathways and cell proliferation. This protein also interacts with amyloid precursor protein (APP) and suppresses the production of amyloid beta (Abeta). Multiple alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Aug 2011]

CD74 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.943

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD74	NM_001025159.3 link	c.137G>T	p.Arg46Leu	missense_variant	Exon 2 of 9	ENST00000009530.13	NP_001020330.1	P04233-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD74	ENST00000009530.13 link	c.137G>T	p.Arg46Leu	missense_variant	Exon 2 of 9	2	NM_001025159.3	ENSP00000009530.7		P04233-1

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151854

Hom.:

Cov.:

show subpopulations

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:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000211

AC:

AN:

237298

Hom.:

AF XY:

0.0000233

AC XY:

AN XY:

128550

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000466

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000549

AC:

AN:

1455880

Hom.:

Cov.:

AF XY:

0.00000691

AC XY:

AN XY:

723772

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000721

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151854

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74132

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000412

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.084

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

.;.;T;D

Eigen

Benign

0.053

Eigen_PC

Benign

-0.0016

FATHMM_MKL

Benign

0.50

LIST_S2

Uncertain

0.91

D;D;D;D

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.94

D;D;D;D

MetaSVM

Uncertain

-0.11

MutationAssessor

Uncertain

2.6

M;M;.;M

PrimateAI

Benign

0.35

PROVEAN

Pathogenic

-4.4

D;D;D;D

REVEL

Uncertain

0.32

Sift

Uncertain

0.0060

D;D;D;D

Sift4G

Uncertain

0.025

D;D;D;D

Polyphen

0.52

P;P;.;D

Vest4

0.69

MutPred

0.83

Gain of ubiquitination at K43 (P = 0.0528);Gain of ubiquitination at K43 (P = 0.0528);Gain of ubiquitination at K43 (P = 0.0528);Gain of ubiquitination at K43 (P = 0.0528);

MVP

0.70

MPC

1.5

ClinPred

0.92

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.19

gMVP

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over