NM_178455.3:c.231C>G

Variant names:

• chr20-45723995-C-G
• rs200862274
• NM_178455.3:c.231C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_178455.3(SPINT4):​c.231C>G​(p.Asn77Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,610,144 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 (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SPINT4 NM_178455.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.08
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957

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.231C>G	p.Asn77Lys	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.231C>G	p.Asn77Lys	missense	Exon 2 of 3	ENSP00000279058.3	Q6UDR6

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458028 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 725274

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33002

American (AMR) AF: 0.00 AC: 0 AN: 43850

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39574

South Asian (SAS) AF: 0.00 AC: 0 AN: 85258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110926

Other (OTH) AF: 0.00 AC: 0 AN: 60234

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152116 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74296

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15280

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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	Pathogenic	0.68
BayesDel_addAF	Benign	-0.0047	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.42	T
PhyloP100		1.1
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.83		Gain of solvent accessibility (P = 0.0221)
MVP		0.84
MPC		0.94
ClinPred		1.0	D
GERP RS		1.5
Varity_R		0.78
gMVP		0.98
Mutation Taster		=58/42	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200862274; hg19: chr20-44352634;