16-84130111-C-A

Variant names:

• chr16-84130111-C-A
• rs756268971
• NM_031463.5:c.541G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_031463.5(HSDL1):​c.541G>T​(p.Ala181Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A181T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HSDL1 NM_031463.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.93
• Publications: 0 publications found

Genes affected

HSDL1 (HGNC:16475): (hydroxysteroid dehydrogenase like 1) Predicted to enable oxidoreductase activity. Located in intermediate filament cytoskeleton and mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.852

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSDL1	NM_031463.5	c.541G>T	p.Ala181Ser	missense_variant	Exon 4 of 6	ENST00000219439.9	NP_113651.4
HSDL1	NM_001146051.2	c.376G>T	p.Ala126Ser	missense_variant	Exon 5 of 7		NP_001139523.1
HSDL1	XM_005256189.4	c.541G>T	p.Ala181Ser	missense_variant	Exon 4 of 6		XP_005256246.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSDL1	ENST00000219439.9	c.541G>T	p.Ala181Ser	missense_variant	Exon 4 of 6	1	NM_031463.5	ENSP00000219439.4
HSDL1	ENST00000434463.7	c.376G>T	p.Ala126Ser	missense_variant	Exon 5 of 7	2		ENSP00000407437.3
HSDL1	ENST00000568857.5	c.*208G>T		downstream_gene_variant		4		ENSP00000457026.1
HSDL1	ENST00000562224.1	c.*217G>T		downstream_gene_variant		4		ENSP00000455797.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.84	T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Benign	1.5	L;.
PhyloP100		2.9
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.5	N;N
REVEL	Uncertain	0.55
Sift	Uncertain	0.015	D;D
Sift4G	Uncertain	0.051	T;D
Polyphen		0.89	P;.
Vest4		0.58
MutPred		0.71		Loss of helix (P = 0.1299);.;
MVP		0.88
MPC		0.18
ClinPred		0.91	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.59

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

Other links and lift over

dbSNP: rs756268971; hg19: chr16-84163716;