19-39369958-A-T

Variant names:

• chr19-39369958-A-T
• rs759759274
• NM_001384574.2:c.500A>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001384574.2(SAMD4B):​c.500A>T​(p.His167Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,574 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: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SAMD4B NM_001384574.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.04

Genes affected

SAMD4B (HGNC:25492): (sterile alpha motif domain containing 4B) Enables RNA binding activity. Predicted to be involved in nuclear-transcribed mRNA poly(A) tail shortening. Predicted to act upstream of or within cerebellar neuron development. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2965219).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SAMD4B	NM_001384574.2	c.500A>T	p.His167Leu	missense_variant	Exon 4 of 14	ENST00000610417.5	NP_001371503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SAMD4B	ENST00000610417.5	c.500A>T	p.His167Leu	missense_variant	Exon 4 of 14	2	NM_001384574.2	ENSP00000484229.1
SAMD4B	ENST00000596368.1	c.500A>T	p.His167Leu	missense_variant	Exon 2 of 5	5		ENSP00000471509.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461574 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727078

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.500A>T (p.H167L) alteration is located in exon 6 (coding exon 2) of the SAMD4B gene. This alteration results from a A to T substitution at nucleotide position 500, causing the histidine (H) at amino acid position 167 to be replaced by a leucine (L). 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	0.11
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.16	T;T;.;T;T;T
Eigen	Benign	0.025
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	D;.;T;D;D;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.30	T;T;T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.5	.;M;.;M;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.8	.;D;.;.;.;.
REVEL	Benign	0.14
Sift	Uncertain	0.0050	.;D;.;.;.;.
Sift4G	Uncertain	0.011	D;D;D;D;D;D
Polyphen		0.0020	.;B;.;B;.;.
Vest4		0.41
MutPred		0.28		Loss of catalytic residue at H167 (P = 0.0923);Loss of catalytic residue at H167 (P = 0.0923);Loss of catalytic residue at H167 (P = 0.0923);Loss of catalytic residue at H167 (P = 0.0923);Loss of catalytic residue at H167 (P = 0.0923);Loss of catalytic residue at H167 (P = 0.0923);
MVP		0.11
MPC		1.3
ClinPred		0.98	D
GERP RS		4.2
Varity_R		0.50
gMVP		0.69

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

Publications

LitVar

Other links and lift over

dbSNP: rs759759274; hg19: chr19-39860598;