14-99652590-C-A

Variant names:

• chr14-99652590-C-A
• rs140080680
• NM_001127258.3:c.622C>A

Variant summary

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

The NM_001127258.3(HHIPL1):​c.622C>A​(p.Arg208Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,808 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. R208H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HHIPL1 NM_001127258.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.64
• Publications: 3 publications found

Genes affected

HHIPL1 (HGNC:19710): (HHIP like 1) This gene encodes a protein that belongs to the glucose/sorbosone dehydrogenase family. The encoded protein also contains a domain that binds folate and reduced folic acid derivatives. [provided by RefSeq, Jul 2016]

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, 0.875

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127258.3. 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
	HHIPL1	NM_001127258.3	MANE Select	c.622C>A	p.Arg208Ser	missense	Exon 2 of 9	NP_001120730.1	F1T0G3
	HHIPL1	NM_032425.5		c.622C>A	p.Arg208Ser	missense	Exon 2 of 8	NP_115801.3	Q96JK4-2
	HHIPL1	NM_001329411.2		c.427C>A	p.Arg143Ser	missense	Exon 3 of 9	NP_001316340.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HHIPL1	ENST00000330710.10	TSL:1 MANE Select	c.622C>A	p.Arg208Ser	missense	Exon 2 of 9	ENSP00000330601.5	Q96JK4-1
	HHIPL1	ENST00000357223.2	TSL:1	c.622C>A	p.Arg208Ser	missense	Exon 2 of 8	ENSP00000349757.2	Q96JK4-2
	HHIPL1	ENST00000949017.1		c.622C>A	p.Arg208Ser	missense	Exon 2 of 9	ENSP00000619076.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460808 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726680

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52720

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111790

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.092	T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-0.85	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		1.6
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.65		Loss of methylation at R208 (P = 0.0486)
MVP		0.48
MPC		1.3
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.94
gMVP		0.97
Mutation Taster		=38/62	disease causing

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: rs140080680; hg19: chr14-100118927; COSMIC: COSV58093277;