6-130145380-A-G

Position:

• chr6-130145380-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001017373.4(SAMD3):​c.1238T>C​(p.Phe413Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,459,560 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: 0.0000027 (0 hom.)
• Consequence: SAMD3 NM_001017373.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.00

Genes affected

SAMD3 (HGNC:21574): (sterile alpha motif domain containing 3)

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.771

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SAMD3	NM_001017373.4	c.1238T>C	p.Phe413Ser	missense_variant	11/12	ENST00000439090.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SAMD3	ENST00000439090.7	c.1238T>C	p.Phe413Ser	missense_variant	11/12	2	NM_001017373.4	P1
	ENST00000622734.1	n.213T>C		non_coding_transcript_exon_variant	2/5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459560 Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2 AN XY: 726098

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 06, 2023

The c.1238T>C (p.F413S) alteration is located in exon 11 (coding exon 9) of the SAMD3 gene. This alteration results from a T to C substitution at nucleotide position 1238, causing the phenylalanine (F) at amino acid position 413 to be replaced by a serine (S). 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	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T;.;T;T
Eigen	Benign	-0.083
Eigen_PC	Benign	0.029
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.77	.;T;.;T
M_CAP	Benign	0.015	T
MetaRNN	Pathogenic	0.77	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M;.;M;M
MutationTaster	Benign	0.92	D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.4	N;N;N;N
REVEL	Benign	0.26
Sift	Benign	0.053	T;D;T;T
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.079	B;.;B;B
Vest4		0.92
MutPred		0.65		Gain of glycosylation at F413 (P = 0.0362);.;Gain of glycosylation at F413 (P = 0.0362);Gain of glycosylation at F413 (P = 0.0362);
MVP		0.74
MPC		0.067
ClinPred		0.94	D
GERP RS		3.8
Varity_R		0.20
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1788527354; hg19: chr6-130466525;