9-5892542-C-A

Variant summary

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

The NM_005511.2(MLANA):c.68C>A(p.Thr23Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,210 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T23M) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: MLANA NM_005511.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.47

Genes affected

MLANA (HGNC:7124): (melan-A) Located in endoplasmic reticulum membrane; melanosome; and trans-Golgi network. [provided by Alliance of Genome Resources, Apr 2022]

KIAA2026 (HGNC:23378): (bromodomain containing 10)

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, 0.756

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLANA	NM_005511.2	c.68C>A	p.Thr23Lys	missense_variant	2/5	ENST00000381477.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLANA	ENST00000381477.8	c.68C>A	p.Thr23Lys	missense_variant	2/5	1	NM_005511.2	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74360

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

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

Nov 08, 2021

The c.68C>A (p.T23K) alteration is located in exon 2 (coding exon 1) of the MLANA gene. This alteration results from a C to A substitution at nucleotide position 68, causing the threonine (T) at amino acid position 23 to be replaced by a lysine (K). 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	0.18
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D;D;D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.76	D;D;D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Uncertain	2.3	M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Benign	0.18
Sift	Benign	0.031	D;D;D
Sift4G	Uncertain	0.046	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.78
MutPred		0.22		Gain of ubiquitination at T23 (P = 0.0042);Gain of ubiquitination at T23 (P = 0.0042);Gain of ubiquitination at T23 (P = 0.0042);
MVP		0.19
MPC		0.95
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.45
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs760218624; hg19: chr9-5892542;