NM_003710.4:c.434T>C

Variant names:

• chr15-40844988-T-C
• rs755644673
• NM_003710.4:c.434T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003710.4(SPINT1):​c.434T>C​(p.Val145Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: SPINT1 NM_003710.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.10
• Publications: 0 publications found

Genes affected

SPINT1 (HGNC:11246): (serine peptidase inhibitor, Kunitz type 1) The protein encoded by this gene is a member of the Kunitz family of serine protease inhibitors. The protein is a potent inhibitor specific for HGF activator and is thought to be involved in the regulation of the proteolytic activation of HGF in injured tissues. Alternative splicing results in multiple variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3060013).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003710.4. 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
	SPINT1	NM_003710.4	MANE Select	c.434T>C	p.Val145Ala	missense	Exon 2 of 11	NP_003701.1	O43278-2
	SPINT1	NM_001386873.1		c.434T>C	p.Val145Ala	missense	Exon 2 of 11	NP_001373802.1	O43278-1
	SPINT1	NM_181642.3		c.434T>C	p.Val145Ala	missense	Exon 2 of 11	NP_857593.1	O43278-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINT1	ENST00000562057.6	TSL:1 MANE Select	c.434T>C	p.Val145Ala	missense	Exon 2 of 11	ENSP00000457076.1	O43278-2
	SPINT1	ENST00000344051.8	TSL:1	c.434T>C	p.Val145Ala	missense	Exon 2 of 11	ENSP00000342098.4	O43278-1
	SPINT1	ENST00000920945.1		c.434T>C	p.Val145Ala	missense	Exon 2 of 11	ENSP00000591004.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000404 AC: 1 AN: 247400 AF XY: 0.00

Gnomad AFR exome AF: 0.0000622

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000753 AC: 11 AN: 1460874 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 726666

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53020

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111556

Other (OTH) AF: 0.0000828 AC: 5 AN: 60358

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152154 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74320

African (AFR) AF: 0.0000241 AC: 1 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15266

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	Benign	0.27
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	23
DANN	Benign	0.82
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.70	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.31	T
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		2.1
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.51
Sift	Benign	0.055	T
Sift4G	Benign	0.10	T
Polyphen		0.85	P
Vest4		0.44
MutPred		0.44		Gain of sheet (P = 0.0125)
MVP		0.98
MPC		0.35
ClinPred		0.42	T
GERP RS		5.5
PromoterAI		-0.039	Neutral
Varity_R		0.30
gMVP		0.78
Mutation Taster		=66/34	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: rs755644673; hg19: chr15-41137186;