12-48569174-G-A

Position:

• chr12-48569174-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000301046.6(LALBA):​c.200C>T​(p.Thr67Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000252 in 1,613,246 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: LALBA ENST00000301046.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0920

Genes affected

LALBA (HGNC:6480): (lactalbumin alpha) This gene encodes alpha-lactalbumin, a principal protein of milk. Alpha-lactalbumin forms the regulatory subunit of the lactose synthase (LS) heterodimer and beta 1,4-galactosyltransferase (beta4Gal-T1) forms the catalytic component. Together, these proteins enable LS to produce lactose by transfering galactose moieties to glucose. As a monomer, alpha-lactalbumin strongly binds calcium and zinc ions and may possess bactericidal or antitumor activity. A folding variant of alpha-lactalbumin, called HAMLET, likely induces apoptosis in tumor and immature cells. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23619989).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LALBA	NM_002289.3	c.200C>T	p.Thr67Met	missense_variant	2/4	ENST00000301046.6	NP_002280.1
LALBA	NM_001384350.1	c.200C>T	p.Thr67Met	missense_variant	3/5		NP_001371279.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LALBA	ENST00000301046.6	c.200C>T	p.Thr67Met	missense_variant	2/4	1	NM_002289.3	ENSP00000301046	P1
LALBA	ENST00000549817.1	c.200C>T	p.Thr67Met	missense_variant	2/3	5		ENSP00000449780

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000151 AC: 38 AN: 251122 Hom.: 0 AF XY: 0.000133 AC XY: 18 AN XY: 135718

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000262 AC: 383 AN: 1461102 Hom.: 0 Cov.: 31 AF XY: 0.000254 AC XY: 185 AN XY: 726930

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.000727

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000285

Gnomad4 OTH exome AF: 0.000613

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74320

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000211 Hom.: 0

Bravo AF: 0.000174

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000181 AC: 22

EpiCase AF: 0.000382

EpiControl AF: 0.000119

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

Dec 14, 2022

The c.200C>T (p.T67M) alteration is located in exon 2 (coding exon 2) of the LALBA gene. This alteration results from a C to T substitution at nucleotide position 200, causing the threonine (T) at amino acid position 67 to be replaced by a methionine (M). 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	0.099
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D;.
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Pathogenic	3.6	H;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Benign	0.20
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.014	D;D
Polyphen		1.0	D;.
Vest4		0.17
MVP		0.81
MPC		1.4
ClinPred		0.90	D
GERP RS		0.038
Varity_R		0.58
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs146052709; hg19: chr12-48962957;