19-7670300-G-T

Variant names:

• chr19-7670300-G-T
• rs2032479485
• NM_020415.4:c.278G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_020415.4(RETN):​c.278G>T​(p.Cys93Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000696 in 1,435,758 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C93Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: RETN NM_020415.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.73
• Publications: 0 publications found

Genes affected

RETN (HGNC:20389): (resistin) This gene belongs to the family defined by the mouse resistin-like genes. The characteristic feature of this family is the C-terminal stretch of 10 cys residues with identical spacing. The mouse homolog of this protein is secreted by adipocytes, and may be the hormone potentially linking obesity to type II diabetes. The encoded protein also has an antimicrobial role in skin, displaying antibacterial activity against both Gram positive and Gram negative bacteria. Alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2020]

RETN Gene-Disease associations (from GenCC):

• diabetes mellitus, noninsulin-dependent

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020415.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RETN	NM_020415.4	MANE Select	c.278G>T	p.Cys93Phe	missense	Exon 4 of 4	NP_065148.1	Q9HD89-1
	RETN	NM_001385726.1		c.320G>T	p.Cys107Phe	missense	Exon 4 of 4	NP_001372655.1
	RETN	NM_001193374.2		c.278G>T	p.Cys93Phe	missense	Exon 4 of 4	NP_001180303.1	Q9HD89-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RETN	ENST00000221515.6	TSL:1 MANE Select	c.278G>T	p.Cys93Phe	missense	Exon 4 of 4	ENSP00000221515.1	Q9HD89-1
	RETN	ENST00000381324.2	TSL:1	c.200G>T	p.Cys67Phe	missense	Exon 2 of 2	ENSP00000370725.2	Q9HD89-2
	RETN	ENST00000629642.1	TSL:5	c.200G>T	p.Cys67Phe	missense	Exon 3 of 3	ENSP00000485998.1	Q9HD89-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1435758 Hom.: 0 Cov.: 37 AF XY: 0.00000140 AC XY: 1 AN XY: 713170

⚠️ 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: 33152

American (AMR) AF: 0.00 AC: 0 AN: 42568

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25752

East Asian (EAS) AF: 0.00 AC: 0 AN: 39000

South Asian (SAS) AF: 0.00 AC: 0 AN: 83590

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42080

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 9.06e-7 AC: 1 AN: 1104248

Other (OTH) AF: 0.00 AC: 0 AN: 59648

⚠️ 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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	-0.032	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		3.7
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-10	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.68
MutPred		0.95		Loss of disorder (P = 0.019)
MVP		0.82
MPC		1.3
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.82
gMVP		0.79
Mutation Taster		=79/21	polymorphism

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: rs2032479485; hg19: chr19-7735186;