chr18-63960318-G-T

Position:

• chr18-63960318-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001123366.2(HMSD):​c.383G>T​(p.Ser128Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HMSD NM_001123366.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0900

Genes affected

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]

HMSD (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08709955).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMSD	NM_001123366.2	c.383G>T	p.Ser128Ile	missense_variant	4/4	ENST00000408945.5	NP_001116838.1
HMSD	XM_017025710.2	c.340+43G>T		intron_variant			XP_016881199.1
HMSD	XM_011525930.3	c.340+43G>T		intron_variant			XP_011524232.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMSD	ENST00000408945.5	c.383G>T	p.Ser128Ile	missense_variant	4/4	3	NM_001123366.2	ENSP00000386207.3
HMSD	ENST00000481726.1	n.312+43G>T		intron_variant		5
HMSD	ENST00000498680.1	n.94+43G>T		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2021

The c.383G>T (p.S128I) alteration is located in exon 4 (coding exon 3) of the HMSD gene. This alteration results from a G to T substitution at nucleotide position 383, causing the serine (S) at amino acid position 128 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	3.7
DANN	Benign	0.90
DEOGEN2	Benign	0.067	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.087	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.69	N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.18
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.074	T
Polyphen		0.0010	B
Vest4		0.14
MutPred		0.53		Loss of sheet (P = 0.0025);
MVP		0.12
MPC		0.29
ClinPred		0.085	T
GERP RS		1.1
Varity_R		0.096
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1000847532; hg19: chr18-61627552;