18-63954451-A-C

Variant names:

• chr18-63954451-A-C
• rs759290376
• NM_001123366.2:c.116A>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001123366.2(HMSD):​c.116A>C​(p.His39Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,086 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.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HMSD NM_001123366.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.39

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMSD	NM_001123366.2	c.116A>C	p.His39Pro	missense_variant	Exon 3 of 4	ENST00000408945.5	NP_001116838.1
HMSD	XM_017025710.2	c.116A>C	p.His39Pro	missense_variant	Exon 3 of 5		XP_016881199.1
HMSD	XM_011525930.3	c.116A>C	p.His39Pro	missense_variant	Exon 3 of 5		XP_011524232.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMSD	ENST00000408945.5	c.116A>C	p.His39Pro	missense_variant	Exon 3 of 4	3	NM_001123366.2	ENSP00000386207.3
HMSD	ENST00000526932.1	c.13A>C	p.Ile5Leu	missense_variant	Exon 1 of 2	3		ENSP00000431632.1
HMSD	ENST00000481726.1	n.88A>C		non_coding_transcript_exon_variant	Exon 2 of 6	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248932 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135278

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460086 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726406

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000830 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	18
DANN	Benign	0.78
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.42	N
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.0098	T
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.75	T
MutationAssessor	Pathogenic	3.4	M
PrimateAI	Benign	0.32	T
PROVEAN	Pathogenic	-9.6	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.61
MutPred		0.82		Loss of helix (P = 0.1299);
MVP		0.39
MPC		1.1
ClinPred		0.66	D
GERP RS		2.0
Varity_R		0.58
gMVP		0.47

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: rs759290376; hg19: chr18-61621685;