5-163463900-G-T

Position:

• chr5-163463900-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001142556.2(HMMR):​c.91G>T​(p.Val31Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000149 in 1,342,274 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: HMMR NM_001142556.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.21

Genes affected

HMMR (HGNC:5012): (hyaluronan mediated motility receptor) The protein encoded by this gene is involved in cell motility. It is expressed in breast tissue and together with other proteins, it forms a complex with BRCA1 and BRCA2, thus is potentially associated with higher risk of breast cancer. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Dec 2008]

HMMR (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08506146).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMMR	NM_001142556.2	c.91G>T	p.Val31Leu	missense_variant	2/18	ENST00000393915.9	NP_001136028.1
HMMR	NM_012484.3	c.91G>T	p.Val31Leu	missense_variant	2/18		NP_036616.2
HMMR	NM_012485.3	c.91G>T	p.Val31Leu	missense_variant	2/17		NP_036617.2
HMMR	NM_001142557.2	c.12+3162G>T		intron_variant			NP_001136029.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMMR	ENST00000393915.9	c.91G>T	p.Val31Leu	missense_variant	2/18	1	NM_001142556.2	ENSP00000377492.4
HMMR	ENST00000520345	c.-207G>T		5_prime_UTR_variant	2/6	2		ENSP00000428481.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000149 AC: 2 AN: 1342274 Hom.: 0 Cov.: 22 AF XY: 0.00000300 AC XY: 2 AN XY: 666878

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000190

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Dec 09, 2023

The c.91G>T (p.V31L) alteration is located in exon 2 (coding exon 2) of the HMMR gene. This alteration results from a G to T substitution at nucleotide position 91, causing the valine (V) at amino acid position 31 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	0.16
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Benign	0.17	.;.;T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.61	T;T;T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.085	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.9	M;M;M
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.36	N;N;N
REVEL	Benign	0.053
Sift	Benign	0.47	T;T;T
Sift4G	Benign	0.48	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.14
MutPred		0.15		Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);
MVP		0.41
MPC		0.077
ClinPred		0.044	T
GERP RS		2.6
Varity_R		0.023
gMVP		0.069

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

Publications

LitVar

Other links and lift over

dbSNP: rs754368124; hg19: chr5-162890906;