12-7479937-G-T

Position:

• chr12-7479937-G-T

Variant summary

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

The ENST00000359156.8(CD163):​c.3403C>A​(p.Leu1135Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00188 in 1,612,580 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0097 (27 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (15 hom.)
• Consequence: CD163 ENST00000359156.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0710

Genes affected

CD163 (HGNC:1631): (CD163 molecule) The protein encoded by this gene is a member of the scavenger receptor cysteine-rich (SRCR) superfamily, and is exclusively expressed in monocytes and macrophages. It functions as an acute phase-regulated receptor involved in the clearance and endocytosis of hemoglobin/haptoglobin complexes by macrophages, and may thereby protect tissues from free hemoglobin-mediated oxidative damage. This protein may also function as an innate immune sensor for bacteria and inducer of local inflammation. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Aug 2011]

CD163L1 (HGNC:30375): (CD163 molecule like 1) This gene encodes a member of the scavenger receptor cysteine-rich (SRCR) superfamily. Members of this family are secreted or membrane-anchored proteins mainly found in cells associated with the immune system. The SRCR family is defined by a 100-110 amino acid SRCR domain, which may mediate protein-protein interaction and ligand binding. The encoded protein contains twelve SRCR domains, a transmembrane region and a cytoplasmic domain. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2014]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031341016).
• BP6: Variant 12-7479937-G-T is Benign according to our data. Variant chr12-7479937-G-T is described in ClinVar as [Benign]. Clinvar id is 785392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00973 (1481/152176) while in subpopulation AFR AF= 0.0337 (1398/41520). AF 95% confidence interval is 0.0322. There are 27 homozygotes in gnomad4. There are 725 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD163	NM_203416.4	c.3344-24C>A		intron_variant		ENST00000432237.3	NP_981961.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD163	ENST00000432237.3	c.3344-24C>A		intron_variant		1	NM_203416.4	ENSP00000403885	P1

Frequencies

GnomAD3 genomes AF: 0.00965 AC: 1468 AN: 152058 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.0335

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00239 AC: 596 AN: 249822 Hom.: 5 AF XY: 0.00178 AC XY: 240 AN XY: 135042

Gnomad AFR exome AF: 0.0307

Gnomad AMR exome AF: 0.00172

Gnomad ASJ exome AF: 0.000398

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000230

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000168

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.00107 AC: 1557 AN: 1460404 Hom.: 15 Cov.: 31 AF XY: 0.000954 AC XY: 693 AN XY: 726534

Gnomad4 AFR exome AF: 0.0349

Gnomad4 AMR exome AF: 0.00208

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000115

Gnomad4 OTH exome AF: 0.00230

GnomAD4 genome AF: 0.00973 AC: 1481 AN: 152176 Hom.: 27 Cov.: 32 AF XY: 0.00975 AC XY: 725 AN XY: 74394

Gnomad4 AFR AF: 0.0337

Gnomad4 AMR AF: 0.00380

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00152 Hom.: 3

Bravo AF: 0.0109

ESP6500AA AF: 0.0313 AC: 138

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00278 AC: 337

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 16, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.084	T;T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.47	T;T
MetaRNN	Benign	0.0031	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.69	N;.
MutationTaster	Benign	1.0	D;D;D;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.010	N;N
REVEL	Benign	0.029
Sift	Benign	0.59	T;D
Sift4G	Benign	0.34	T;T
Polyphen		0.19	B;.
Vest4		0.21
MVP		0.44
MPC		0.50
ClinPred		0.029	T
GERP RS		0.97
Varity_R		0.048
gMVP		0.040

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: rs74056488; hg19: chr12-7632533;