7-23299444-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_138446.2(MALSU1):c.92A>C(p.Glu31Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MALSU1 NM_138446.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.640

Genes affected

MALSU1 (HGNC:21721): (mitochondrial assembly of ribosomal large subunit 1) Predicted to enable ribosomal large subunit binding activity. Involved in negative regulation of mitochondrial translation and ribosomal large subunit biogenesis. Located in cytosol and mitochondrion. Colocalizes with mitochondrial large ribosomal subunit. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03916076).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MALSU1	NM_138446.2	c.92A>C	p.Glu31Ala	missense_variant	1/4	ENST00000466681.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MALSU1	ENST00000466681.2	c.92A>C	p.Glu31Ala	missense_variant	1/4	1	NM_138446.2	P1
MALSU1	ENST00000287543.4	n.106A>C		non_coding_transcript_exon_variant	1/3	2
MALSU1	ENST00000481564.1	n.104A>C		non_coding_transcript_exon_variant	1/2	2
MALSU1	ENST00000479974.1	n.411+295A>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453882 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 723380

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

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

Sep 22, 2023

The c.92A>C (p.E31A) alteration is located in exon 1 (coding exon 1) of the MALSU1 gene. This alteration results from a A to C substitution at nucleotide position 92, causing the glutamic acid (E) at amino acid position 31 to be replaced by an alanine (A). 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	0.062
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	0.52
Dann	Benign	0.41
DEOGEN2	Benign	0.028	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.0080
Sift	Benign	1.0	T
Sift4G	Benign	0.77	T
Polyphen		0.0	B
Vest4		0.068
MutPred		0.18		Gain of MoRF binding (P = 0.0416);
MVP		0.13
MPC		0.064
ClinPred		0.060	T
GERP RS		-2.3
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
Varity_R		0.033
gMVP		0.36

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: rs1010031970; hg19: chr7-23339063;