19-39369655-C-T

Variant names:

• chr19-39369655-C-T
• rs2077176878
• NM_001384574.2:c.197C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001384574.2(SAMD4B):​c.197C>T​(p.Ala66Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SAMD4B NM_001384574.2 missense, splice_region
• Scores: Splicing: ADA: 0.9955
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.51
• Publications: 0 publications found

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]

RN7SL566P (HGNC:46582): (RNA, 7SL, cytoplasmic 566, pseudogene)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384574.2. 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
	SAMD4B	NM_001384574.2	MANE Select	c.197C>T	p.Ala66Val	missense splice_region	Exon 4 of 14	NP_001371503.1	Q5PRF9
	SAMD4B	NM_001384565.1		c.197C>T	p.Ala66Val	missense splice_region	Exon 4 of 14	NP_001371494.1	Q5PRF9
	SAMD4B	NM_001384566.1		c.197C>T	p.Ala66Val	missense splice_region	Exon 5 of 15	NP_001371495.1	Q5PRF9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SAMD4B	ENST00000610417.5	TSL:2 MANE Select	c.197C>T	p.Ala66Val	missense splice_region	Exon 4 of 14	ENSP00000484229.1	Q5PRF9
	SAMD4B	ENST00000314471.10	TSL:1	c.197C>T	p.Ala66Val	missense splice_region	Exon 6 of 16	ENSP00000317224.5	Q5PRF9
	SAMD4B	ENST00000598913.5	TSL:1	c.197C>T	p.Ala66Val	missense splice_region	Exon 3 of 13	ENSP00000470237.1	M0QZ22

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

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	0.14
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.033	T
Eigen	Benign	0.040
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.5
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.12
Sift	Benign	0.17	T
Sift4G	Benign	0.19	T
Polyphen		0.034	B
Vest4		0.33
MutPred		0.59		Loss of helix (P = 0.0041)
MVP		0.15
MPC		0.71
ClinPred		0.53	D
GERP RS		5.7
PromoterAI		-0.0083	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.35
Mutation Taster		=42/58	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.89
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: rs2077176878; hg19: chr19-39860295;