4-70362159-C-A

Variant names:

• chr4-70362159-C-A
• rs1016313924
• NM_012390.4:c.44C>A

Variant summary

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

The NM_012390.4(SMR3A):​c.44C>A​(p.Ala15Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A15G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SMR3A NM_012390.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.07
• Publications: 0 publications found

Genes affected

SMR3A (HGNC:19216): (submaxillary gland androgen regulated protein 3A) Predicted to enable endopeptidase inhibitor activity. Predicted to be involved in regulation of sensory perception of pain. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000308728 (HGNC:58805):

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=0.15925229).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012390.4. 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
	SMR3A	NM_012390.4	MANE Select	c.44C>A	p.Ala15Glu	missense	Exon 2 of 3	NP_036522.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMR3A	ENST00000226460.5	TSL:1 MANE Select	c.44C>A	p.Ala15Glu	missense	Exon 2 of 3	ENSP00000226460.4	Q99954
	ENSG00000308728	ENST00000836001.1		n.198+798G>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459826 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 726262

African (AFR) AF: 0.00 AC: 0 AN: 33346

American (AMR) AF: 0.0000224 AC: 1 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26056

East Asian (EAS) AF: 0.00 AC: 0 AN: 39602

South Asian (SAS) AF: 0.00 AC: 0 AN: 86200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110518

Other (OTH) AF: 0.00 AC: 0 AN: 60266

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	7.8
DANN	Benign	0.37
DEOGEN2	Benign	0.044	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.8	L
PhyloP100		-1.1
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.099
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.25	T
Polyphen		0.020	B
Vest4		0.43
MutPred		0.32		Gain of solvent accessibility (P = 0.0145)
MVP		0.16
MPC		0.070
ClinPred		0.093	T
GERP RS		-0.62
Varity_R		0.24
gMVP		0.11
Mutation Taster		=97/3	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: rs1016313924; hg19: chr4-71227876; COSMIC: COSV99895887;