NM_001044305.3:c.617C>T

Variant names:

• chr6-70836981-C-T
• rs1000161287
• NM_001044305.3:c.617C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001044305.3(SMAP1):​c.617C>T​(p.Thr206Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000187 in 1,603,380 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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: 0.0000014 (0 hom.)
• Consequence: SMAP1 NM_001044305.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.48
• Publications: 0 publications found

Genes affected

SMAP1 (HGNC:19651): (small ArfGAP 1) The protein encoded by this gene is similar to the mouse stromal membrane-associated protein-1. This similarity suggests that this human gene product is also a type II membrane glycoprotein involved in the erythropoietic stimulatory activity of stromal cells. Alternate splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.090954095).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAP1	NM_001044305.3	c.617C>T	p.Thr206Ile	missense_variant	Exon 7 of 11	ENST00000370455.8	NP_001037770.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAP1	ENST00000370455.8	c.617C>T	p.Thr206Ile	missense_variant	Exon 7 of 11	1	NM_001044305.3	ENSP00000359484.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152096 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: 0.00 AC: 0 AN: 243712 AF XY: 0.00

Gnomad AFR exome AF: 0.00

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: 0.00000138 AC: 2 AN: 1451284 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 721384

African (AFR) AF: 0.00 AC: 0 AN: 32914

American (AMR) AF: 0.00 AC: 0 AN: 43958

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25948

East Asian (EAS) AF: 0.00 AC: 0 AN: 39036

South Asian (SAS) AF: 0.00 AC: 0 AN: 83462

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53010

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107400

Other (OTH) AF: 0.0000167 AC: 1 AN: 59870

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152096 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74294

African (AFR) AF: 0.0000241 AC: 1 AN: 41420

American (AMR) AF: 0.00 AC: 0 AN: 15278

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68010

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 13, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.617C>T (p.T206I) alteration is located in exon 7 (coding exon 7) of the SMAP1 gene. This alteration results from a C to T substitution at nucleotide position 617, causing the threonine (T) at amino acid position 206 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	0.082
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	21
DANN	Benign	0.44
DEOGEN2	Benign	0.021	.;.;T;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.82	T;T;T;T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.091	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	.;.;L;.
PhyloP100		2.5
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.80	N;N;N;.
REVEL	Benign	0.072
Sift	Benign	0.15	T;T;T;.
Sift4G	Benign	0.18	T;T;T;T
Polyphen		0.56	P;B;B;.
Vest4		0.28
MutPred		0.20		.;.;Loss of phosphorylation at T206 (P = 0.0054);.;
MVP		0.18
MPC		0.14
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.053
gMVP		0.097
Mutation Taster		=81/19	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: rs1000161287; hg19: chr6-71546684; COSMIC: COSV106416395;