10-102873124-T-C

Variant names:

• chr10-102873124-T-C
• rs200488263
• NM_020682.4:c.349T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_020682.4(AS3MT):​c.349T>C​(p.Tyr117His) variant causes a missense change. The variant allele was found at a frequency of 0.000297 in 1,601,690 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 0.00014 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: AS3MT NM_020682.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.79
• Publications: 4 publications found

Genes affected

AS3MT (HGNC:17452): (arsenite methyltransferase) AS3MT catalyzes the transfer of a methyl group from S-adenosyl-L-methionine (AdoMet) to trivalent arsenical and may play a role in arsenic metabolism (Lin et al., 2002 [PubMed 11790780]).[supplied by OMIM, Mar 2008]

BORCS7-ASMT (HGNC:49183): (BORCS7-ASMT readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring C10orf32 (chromosome 10 open reading frame 32) and AS3MT (arsenic, +3 oxidation state, methyltransferase) genes. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is therefore unlikely to produce a protein product. [provided by RefSeq, Dec 2010]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11490595).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AS3MT	NM_020682.4	c.349T>C	p.Tyr117His	missense_variant	Exon 5 of 11	ENST00000369880.8	NP_065733.2
BORCS7-ASMT	NR_037644.1	n.754T>C		non_coding_transcript_exon_variant	Exon 9 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AS3MT	ENST00000369880.8	c.349T>C	p.Tyr117His	missense_variant	Exon 5 of 11	1	NM_020682.4	ENSP00000358896.3
BORCS7-ASMT	ENST00000299353.6	n.*356T>C		non_coding_transcript_exon_variant	Exon 9 of 15	5		ENSP00000299353.5
BORCS7-ASMT	ENST00000299353.6	n.*356T>C		3_prime_UTR_variant	Exon 9 of 15	5		ENSP00000299353.5

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152160 Hom.: 0 Cov.: 31

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: 0.000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000169 AC: 40 AN: 237306 AF XY: 0.000140

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000105

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.000327

Gnomad OTH exome AF: 0.000345

GnomAD4 exome AF: 0.000314 AC: 455 AN: 1449530 Hom.: 0 Cov.: 30 AF XY: 0.000302 AC XY: 218 AN XY: 720712

African (AFR) AF: 0.0000611 AC: 2 AN: 32724

American (AMR) AF: 0.00 AC: 0 AN: 40930

Ashkenazi Jewish (ASJ) AF: 0.0000390 AC: 1 AN: 25622

East Asian (EAS) AF: 0.00 AC: 0 AN: 39540

South Asian (SAS) AF: 0.00 AC: 0 AN: 82874

European-Finnish (FIN) AF: 0.0000563 AC: 3 AN: 53326

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

European-Non Finnish (NFE) AF: 0.000399 AC: 442 AN: 1108878

Other (OTH) AF: 0.000117 AC: 7 AN: 59916

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152160 Hom.: 0 Cov.: 31 AF XY: 0.000108 AC XY: 8 AN XY: 74334

African (AFR) AF: 0.0000241 AC: 1 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15260

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.000314 Hom.: 0

Bravo AF: 0.000144

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000367 AC: 3

ExAC AF: 0.000190 AC: 23

EpiCase AF: 0.000383

EpiControl AF: 0.000595

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 04, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.349T>C (p.Y117H) alteration is located in exon 5 (coding exon 5) of the AS3MT gene. This alteration results from a T to C substitution at nucleotide position 349, causing the tyrosine (Y) at amino acid position 117 to be replaced by a histidine (H). 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	0.14
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.076	T;T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	.;L
PhyloP100		3.8
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.0	.;D
REVEL	Benign	0.061
Sift	Benign	0.24	.;T
Polyphen		0.045	.;B
Vest4		0.35
MVP		0.31
MPC		0.55
ClinPred		0.11	T
GERP RS		4.5
Varity_R		0.14
gMVP		0.45

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: rs200488263; hg19: chr10-104632881;