NM_177986.5:c.-52G>A

Variant names:

• chr18-31376860-G-A
• rs112493254
• NM_177986.5:c.-52G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_177986.5(DSG4):​c.-52G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000321 in 1,606,664 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (4 hom.)
• Consequence: DSG4 NM_177986.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.75
• Publications: 0 publications found

Genes affected

DSG4 (HGNC:21307): (desmoglein 4) This gene encodes a member of the desmoglein subgroup of desmosomal cadherins. The encoded preproprotein is proteolytically processed to generate the mature protein. This protein is a transmembrane component of desmosomes and may play a role in cell-cell adhesion in epithelial cells. Mutations in the gene are associated with localized autosomal recessive hypotrichosis and monilethrix, characterized by impaired hair growth. [provided by RefSeq, May 2016]

DSG1-AS1 (HGNC:51115): (DSG1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000269 (41/152280) while in subpopulation SAS AF = 0.0056 (27/4820). AF 95% confidence interval is 0.00395. There are 1 homozygotes in GnomAd4. There are 29 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_177986.5. 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
	DSG4	NM_177986.5	MANE Select	c.-52G>A		5_prime_UTR	Exon 1 of 16	NP_817123.1	Q86SJ6-1
	DSG4	NM_001134453.3		c.-52G>A		5_prime_UTR	Exon 1 of 15	NP_001127925.1	Q86SJ6-2
	DSG1-AS1	NR_110788.1		n.157-22407C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSG4	ENST00000308128.9	TSL:1 MANE Select	c.-52G>A		5_prime_UTR	Exon 1 of 16	ENSP00000311859.4	Q86SJ6-1
	DSG1-AS1	ENST00000578477.6	TSL:3	n.157-12575C>T		intron	N/A
	DSG1-AS1	ENST00000581452.1	TSL:3	n.90-12575C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152162 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00560

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000326 AC: 474 AN: 1454384 Hom.: 4 Cov.: 28 AF XY: 0.000432 AC XY: 313 AN XY: 723942

African (AFR) AF: 0.000300 AC: 10 AN: 33280

American (AMR) AF: 0.0000448 AC: 2 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26042

East Asian (EAS) AF: 0.0000758 AC: 3 AN: 39590

South Asian (SAS) AF: 0.00492 AC: 423 AN: 86052

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53344

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5744

European-Non Finnish (NFE) AF: 0.00000904 AC: 10 AN: 1105588

Other (OTH) AF: 0.000416 AC: 25 AN: 60128

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152280 Hom.: 1 Cov.: 32 AF XY: 0.000389 AC XY: 29 AN XY: 74460

African (AFR) AF: 0.000192 AC: 8 AN: 41566

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00560 AC: 27 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.0000693 Hom.: 0

Bravo AF: 0.000132

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hypotrichosis 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.15
DANN	Benign	0.62
PhyloP100		-1.8
PromoterAI		-0.028	Neutral
Mutation Taster		=300/0	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: rs112493254; hg19: chr18-28956823; COSMIC: COSV100355086; COSMIC: COSV100355086;