chr20-45723925-A-C

Variant names:

• chr20-45723925-A-C
• rs1180175098
• NM_178455.3:c.161A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_178455.3(SPINT4):​c.161A>C​(p.His54Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,450,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SPINT4 NM_178455.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.24
• Publications: 0 publications found

Genes affected

SPINT4 (HGNC:16130): (serine peptidase inhibitor, Kunitz type 4) Predicted to enable serine-type endopeptidase inhibitor activity. Predicted to be involved in negative regulation of endopeptidase activity. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.826

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178455.3. 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
	SPINT4	NM_178455.3	MANE Select	c.161A>C	p.His54Pro	missense	Exon 2 of 3	NP_848550.1	Q6UDR6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINT4	ENST00000279058.4	TSL:1 MANE Select	c.161A>C	p.His54Pro	missense	Exon 2 of 3	ENSP00000279058.3	Q6UDR6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000416 AC: 1 AN: 240262 AF XY: 0.00000770

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000575

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1450872 Hom.: 0 Cov.: 30 AF XY: 0.00000277 AC XY: 2 AN XY: 721682

African (AFR) AF: 0.00 AC: 0 AN: 32232

American (AMR) AF: 0.00 AC: 0 AN: 41546

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25790

East Asian (EAS) AF: 0.0000507 AC: 2 AN: 39410

South Asian (SAS) AF: 0.00 AC: 0 AN: 83572

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53312

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109384

Other (OTH) AF: 0.00 AC: 0 AN: 59906

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	19
DANN	Benign	0.80
DEOGEN2	Benign	0.040	T
Eigen	Benign	-0.072
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.17	T
M_CAP	Benign	0.023	T
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.87	T
PhyloP100		2.2
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.33
Sift	Benign	0.11	T
Sift4G	Benign	0.20	T
Polyphen		1.0	D
Vest4		0.62
MutPred		0.67		Loss of methylation at R56 (P = 0.0846)
MVP		0.74
MPC		1.1
ClinPred		0.38	T
GERP RS		3.9
Varity_R		0.83
gMVP		0.89
Mutation Taster		=80/20	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: rs1180175098; hg19: chr20-44352564;