rs111432786

Variant names:

• chr18-63979886-T-G
• rs111432786
• NM_002640.4:c.254T>G

Your query was ambiguous. Multiple possible variants found:

• chr18-63979886-T-G
• chr18-63979886-T-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001348370.2(SERPINB8):​c.-144T>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,614,068 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00058 (11 hom.)
• Consequence: SERPINB8 NM_001348370.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0610
• Publications: 3 publications found

Genes affected

SERPINB8 (HGNC:8952): (serpin family B member 8) The protein encoded by this gene is a member of the ov-serpin family of serine protease inhibitors. The encoded protein is produced by platelets and can bind to and inhibit the function of furin, a serine protease involved in platelet functions. In addition, this protein has been found to enhance the mechanical stability of cell-cell adhesion in the skin, and defects in this gene have been associated with an autosomal-recessive form of exfoliative ichthyosis. [provided by RefSeq, Jan 2017]

HMSD (HGNC:23037): (histocompatibility minor serpin domain containing) This gene encodes a serpin-domain containing protein that may function as a serine protease inhibitor. This gene is primarily expressed in cells of myeloid lineage. A polymorphism in this gene may result in the expression a splice variant that encodes a minor histocompatibility antigen. [provided by RefSeq, Oct 2010]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011955082).
• BP6: Variant 18-63979886-T-G is Benign according to our data. Variant chr18-63979886-T-G is described in ClinVar as Benign. ClinVar VariationId is 1599386.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 = 0.00595 (907/152314) while in subpopulation AFR AF = 0.0208 (865/41568). AF 95% confidence interval is 0.0197. There are 10 homozygotes in GnomAd4. There are 414 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR,Unknown,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001348370.2. 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
	SERPINB8	NM_002640.4	MANE Select	c.254T>G	p.Leu85Trp	missense	Exon 3 of 7	NP_002631.3
	SERPINB8	NM_001348370.2		c.-144T>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 5	NP_001335299.1
	SERPINB8	NM_001276490.2		c.-293T>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 6	NP_001263419.1	P50452-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINB8	ENST00000397985.7	TSL:1 MANE Select	c.254T>G	p.Leu85Trp	missense	Exon 3 of 7	ENSP00000381072.2	P50452-1
	SERPINB8	ENST00000397988.7	TSL:1	c.254T>G	p.Leu85Trp	missense	Exon 3 of 7	ENSP00000381075.3	P50452-2
	SERPINB8	ENST00000542677.5	TSL:2	c.-293T>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 6	ENSP00000438328.1	P50452-3

Frequencies

GnomAD3 genomes AF: 0.00596 AC: 907 AN: 152196 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0209

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00151 AC: 379 AN: 251316 AF XY: 0.00101

Gnomad AFR exome AF: 0.0212

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000581 AC: 849 AN: 1461754 Hom.: 11 Cov.: 32 AF XY: 0.000503 AC XY: 366 AN XY: 727186

African (AFR) AF: 0.0203 AC: 679 AN: 33468

American (AMR) AF: 0.000648 AC: 29 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.0000360 AC: 40 AN: 1111922

Other (OTH) AF: 0.00142 AC: 86 AN: 60388

GnomAD4 genome AF: 0.00595 AC: 907 AN: 152314 Hom.: 10 Cov.: 32 AF XY: 0.00556 AC XY: 414 AN XY: 74480

African (AFR) AF: 0.0208 AC: 865 AN: 41568

American (AMR) AF: 0.00170 AC: 26 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

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: 0.000132 AC: 9 AN: 68024

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00129 Hom.: 1

Bravo AF: 0.00659

ESP6500AA AF: 0.0184 AC: 81

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00186 AC: 226

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	SERPINB8-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Uncertain	0.50	T
Eigen	Benign	0.059
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		-0.061
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.28
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.021	D
Polyphen		0.99	D
Vest4		0.32
MVP		0.94
MPC		0.12
ClinPred		0.046	T
GERP RS		3.6
PromoterAI		0.015	Neutral
Varity_R		0.42
gMVP		0.37
Mutation Taster		=299/1	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: rs111432786; hg19: chr18-61647120;