14-77468096-T-G

Variant names:

• chr14-77468096-T-G
• rs189777571
• NM_012111.3:c.704T>G

Variant summary

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

The NM_012111.3(AHSA1):​c.704T>G​(p.Phe235Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000199 in 1,506,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 27)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: AHSA1 NM_012111.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.78
• Publications: 0 publications found

Genes affected

AHSA1 (HGNC:1189): (activator of HSP90 ATPase activity 1) Enables ATPase activator activity; Hsp90 protein binding activity; and chaperone binding activity. Involved in positive regulation of ATPase activity. Located in cytosol. [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, 0.911

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012111.3. 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
	AHSA1	NM_012111.3	MANE Select	c.704T>G	p.Phe235Cys	missense	Exon 7 of 9	NP_036243.1	O95433-1
	AHSA1	NM_001321441.2		c.299T>G	p.Phe100Cys	missense	Exon 7 of 9	NP_001308370.1	G3V438

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHSA1	ENST00000216479.8	TSL:1 MANE Select	c.704T>G	p.Phe235Cys	missense	Exon 7 of 9	ENSP00000216479.3	O95433-1
	AHSA1	ENST00000855622.1		c.704T>G	p.Phe235Cys	missense	Exon 7 of 10	ENSP00000525681.1
	AHSA1	ENST00000920448.1		c.764T>G	p.Phe255Cys	missense	Exon 8 of 10	ENSP00000590507.1

Frequencies

GnomAD3 genomes AF: 0.0000133 AC: 2 AN: 149970 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.0000493

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 AF: 7.37e-7 AC: 1 AN: 1356154 Hom.: 0 Cov.: 31 AF XY: 0.00000149 AC XY: 1 AN XY: 670586

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

African (AFR) AF: 0.0000329 AC: 1 AN: 30440

American (AMR) AF: 0.00 AC: 0 AN: 33970

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24596

East Asian (EAS) AF: 0.00 AC: 0 AN: 36028

South Asian (SAS) AF: 0.00 AC: 0 AN: 76706

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49262

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5516

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1043202

Other (OTH) AF: 0.00 AC: 0 AN: 56434

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000133 AC: 2 AN: 150072 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 73206

African (AFR) AF: 0.0000492 AC: 2 AN: 40652

American (AMR) AF: 0.00 AC: 0 AN: 15016

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 5104

South Asian (SAS) AF: 0.00 AC: 0 AN: 4652

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67604

Other (OTH) AF: 0.00 AC: 0 AN: 2046

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000113

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	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		7.8
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-7.5	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.95
MVP		0.78
MPC		2.1
ClinPred		1.0	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.89
gMVP		0.88
Mutation Taster		=6/94	disease causing

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: rs189777571; hg19: chr14-77934439;