7-75544751-T-G

Position:

• chr7-75544751-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005338.7(HIP1):​c.2710A>C​(p.Met904Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HIP1 NM_005338.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.19

Genes affected

HIP1 (HGNC:4913): (huntingtin interacting protein 1) The product of this gene is a membrane-associated protein that functions in clathrin-mediated endocytosis and protein trafficking within the cell. The encoded protein binds to the huntingtin protein in the brain; this interaction is lost in Huntington's disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35437584).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HIP1	NM_005338.7	c.2710A>C	p.Met904Leu	missense_variant	27/31	ENST00000336926.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HIP1	ENST00000336926.11	c.2710A>C	p.Met904Leu	missense_variant	27/31	1	NM_005338.7	P1
HIP1	ENST00000616821.4	c.2623A>C	p.Met875Leu	missense_variant	27/31	1
HIP1	ENST00000434438.6	c.2557A>C	p.Met853Leu	missense_variant	25/29	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 04, 2022

The c.2710A>C (p.M904L) alteration is located in exon 27 (coding exon 27) of the HIP1 gene. This alteration results from a A to C substitution at nucleotide position 2710, causing the methionine (M) at amino acid position 904 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.12	T;.;.
Eigen	Benign	-0.047
Eigen_PC	Benign	0.092
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.76	T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.35	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.41	N;N;.
REVEL	Benign	0.13
Sift	Benign	0.12	T;T;.
Sift4G	Benign	0.073	T;D;T
Polyphen		0.0	B;.;.
Vest4		0.43
MutPred		0.59		Loss of catalytic residue at M904 (P = 5e-04);.;.;
MVP		0.47
MPC		0.32
ClinPred		0.77	D
GERP RS		4.4
Varity_R		0.17
gMVP		0.43

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554490607; hg19: chr7-75174049;