2-171925623-G-A

Position:

• chr2-171925623-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_003642.4(HAT1):​c.94G>A​(p.Ala32Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000226 in 1,329,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: HAT1 NM_003642.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.88

Genes affected

HAT1 (HGNC:4821): (histone acetyltransferase 1) The protein encoded by this gene is a type B histone acetyltransferase (HAT) that is involved in the rapid acetylation of newly synthesized cytoplasmic histones, which are in turn imported into the nucleus for de novo deposition onto nascent DNA chains. Histone acetylation, particularly of histone H4, plays an important role in replication-dependent chromatin assembly. Specifically, this HAT can acetylate soluble but not nucleosomal histone H4 at lysines 5 and 12, and to a lesser degree, histone H2A at lysine 5. Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Jun 2009]

HAT1 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HAT1	NM_003642.4	c.94G>A	p.Ala32Thr	missense_variant	2/11	ENST00000264108.5	NP_003633.2
HAT1	XM_006712808.4	c.76G>A	p.Ala26Thr	missense_variant	3/12		XP_006712871.1
HAT1	NR_027862.2	n.134G>A		non_coding_transcript_exon_variant	2/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HAT1	ENST00000264108.5	c.94G>A	p.Ala32Thr	missense_variant	2/11	1	NM_003642.4	ENSP00000264108.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000226 AC: 3 AN: 1329794 Hom.: 0 Cov.: 20 AF XY: 0.00000299 AC XY: 2 AN XY: 668370

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000512

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000101

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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 10, 2024

The c.94G>A (p.A32T) alteration is located in exon 2 (coding exon 2) of the HAT1 gene. This alteration results from a G to A substitution at nucleotide position 94, causing the alanine (A) at amino acid position 32 to be replaced by a threonine (T). 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	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.0078	T
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	-0.26	T
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.024	D
Vest4		0.80
MutPred		0.90		Loss of ubiquitination at K36 (P = 0.0573);
MVP		0.62
MPC		0.90
ClinPred		0.98	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
gMVP		0.93

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: rs1574030010; hg19: chr2-172782133;