rs773681350

Variant names:

• chr16-728834-A-C
• rs773681350
• NM_032304.4:c.539A>C

Your query was ambiguous. Multiple possible variants found:

• chr16-728834-A-C
• chr16-728834-A-G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_032304.4(HAGHL):​c.539A>C​(p.Glu180Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000244 in 1,599,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: HAGHL NM_032304.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.80
• Publications: 0 publications found

Genes affected

HAGHL (HGNC:14177): (hydroxyacylglutathione hydrolase like) Predicted to enable hydroxyacylglutathione hydrolase activity and metal ion binding activity. Predicted to be involved in methylglyoxal catabolic process to D-lactate via S-lactoyl-glutathione. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1747421).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032304.4. 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
	HAGHL	NM_032304.4	MANE Select	c.539A>C	p.Glu180Ala	missense	Exon 6 of 8	NP_115680.1	Q6PII5-2
	HAGHL	NM_001323636.2		c.539A>C	p.Glu180Ala	missense	Exon 7 of 8	NP_001310565.1
	HAGHL	NM_207112.2		c.539A>C	p.Glu180Ala	missense	Exon 7 of 7	NP_996995.1	Q6PII5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAGHL	ENST00000389703.8	TSL:1 MANE Select	c.539A>C	p.Glu180Ala	missense	Exon 6 of 8	ENSP00000374353.3	Q6PII5-2
	HAGHL	ENST00000389701.9	TSL:1	n.726A>C		non_coding_transcript_exon	Exon 5 of 7
	HAGHL	ENST00000341413.8	TSL:2	c.539A>C	p.Glu180Ala	missense	Exon 7 of 7	ENSP00000341952.4	Q6PII5-1

Frequencies

GnomAD3 genomes AF: 0.0000134 AC: 2 AN: 148920 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000406

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

GnomAD2 exomes AF: 0.0000607 AC: 15 AN: 246918 AF XY: 0.0000520

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000831

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000255 AC: 37 AN: 1450992 Hom.: 0 Cov.: 36 AF XY: 0.0000263 AC XY: 19 AN XY: 721532

African (AFR) AF: 0.00 AC: 0 AN: 33244

American (AMR) AF: 0.00 AC: 0 AN: 44378

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25874

East Asian (EAS) AF: 0.000942 AC: 37 AN: 39290

South Asian (SAS) AF: 0.00 AC: 0 AN: 86008

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51148

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105464

Other (OTH) AF: 0.00 AC: 0 AN: 59862

GnomAD4 genome AF: 0.0000134 AC: 2 AN: 148920 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 1 AN XY: 72566

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 40418

American (AMR) AF: 0.00 AC: 0 AN: 14950

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3432

East Asian (EAS) AF: 0.000406 AC: 2 AN: 4930

South Asian (SAS) AF: 0.00 AC: 0 AN: 4646

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9918

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67356

Other (OTH) AF: 0.00 AC: 0 AN: 2056

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000664 AC: 8

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.037	T
Eigen	Benign	-0.089
Eigen_PC	Benign	-0.057
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.17	T
MetaSVM	Uncertain	0.32	D
MutationAssessor	Benign	0.24	N
PhyloP100		5.8
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.40
Sift	Benign	0.26	T
Sift4G	Benign	0.092	T
Polyphen		0.82	P
Vest4		0.20
MutPred		0.37		Gain of helix (P = 0.062)
MVP		0.68
MPC		0.31
ClinPred		0.17	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.37
Mutation Taster		=69/31	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: rs773681350; hg19: chr16-778834;