NM_016299.4:c.49G>C

Variant names:

• chr10-14838451-G-C
• rs765298056
• NM_016299.4:c.49G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_016299.4(HSPA14):​c.49G>C​(p.Val17Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,452,244 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HSPA14 NM_016299.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.89
• Publications: 1 publications found

Genes affected

HSPA14 (HGNC:29526): (heat shock protein family A (Hsp70) member 14) Predicted to enable several functions, including ATP binding activity; misfolded protein binding activity; and unfolded protein binding activity. Predicted to be involved in several processes, including cellular response to unfolded protein; chaperone cofactor-dependent protein refolding; and protein refolding. Located in cytosol. Colocalizes with ribosome. [provided by Alliance of Genome Resources, Apr 2022]

MSANTD7 (HGNC:56248): (Myb/SANT DNA binding domain containing 7)

CDNF (HGNC:24913): (cerebral dopamine neurotrophic factor) Predicted to enable growth factor activity. Predicted to be involved in dopaminergic neuron differentiation and neuron projection development. Predicted to be active in endoplasmic reticulum and extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016299.4. 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
	HSPA14	NM_016299.4	MANE Select	c.49G>C	p.Val17Leu	missense	Exon 1 of 14	NP_057383.2	Q0VDF9
	MSANTD7	NM_001378785.1	MANE Select	c.-324G>C		5_prime_UTR	Exon 1 of 5	NP_001365714.1	A0A1W2PQ72
	MSANTD7	NM_001378790.1		c.-253G>C		5_prime_UTR	Exon 1 of 4	NP_001365719.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPA14	ENST00000378372.8	TSL:1 MANE Select	c.49G>C	p.Val17Leu	missense	Exon 1 of 14	ENSP00000367623.3	Q0VDF9
	MSANTD7	ENST00000640019.3	TSL:1 MANE Select	c.-324G>C		5_prime_UTR	Exon 1 of 5	ENSP00000491568.1	A0A1W2PQ72
	CDNF	ENST00000378442.5	TSL:1	c.-380C>G		5_prime_UTR	Exon 1 of 6	ENSP00000367703.1	Q49AH0-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000429 AC: 1 AN: 232852 AF XY: 0.00000790

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000103

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1452244 Hom.: 0 Cov.: 31 AF XY: 0.00000416 AC XY: 3 AN XY: 721954

African (AFR) AF: 0.0000299 AC: 1 AN: 33408

American (AMR) AF: 0.00 AC: 0 AN: 43940

Ashkenazi Jewish (ASJ) AF: 0.0000385 AC: 1 AN: 25962

East Asian (EAS) AF: 0.00 AC: 0 AN: 39504

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84864

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5504

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109578

Other (OTH) AF: 0.00 AC: 0 AN: 60086

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000825 AC: 1

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	0.32
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.068	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.42	N
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		1.9
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.19
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.016	D
Polyphen		0.46	P
Vest4		0.57
MutPred		0.80		Loss of sheet (P = 0.0817)
MVP		0.36
MPC		0.35
ClinPred		0.89	D
GERP RS		2.5
PromoterAI		-0.038	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.66
gMVP		0.77
Mutation Taster		=67/33	polymorphism

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: rs765298056; hg19: chr10-14880450;